Chromium-mediated coupling and application to the synthesis of halichondrins

ABSTRACT

The present invention provides unified synthesis of the C1-C19 building blocks of halichondrins and analogs thereof using selective coupling of poly-halogenated nucleophiles in chromium-mediated coupling reactions. The present invention also provides a practical and efficient synthesis of C20-C38 building blocks of halichondrins and analogs thereof. Also provided herein are general methods of selective activation and coupling of poly-halogenated analogs with an aldehyde. The provided coupling reactions are selective for halo-enone and halo-acetylenic ketal over vinyl halide and halide attached to a sp hybridized carbon. The provided efficient selective coupling reactions can allow easy access to the C1-C19 building blocks and C20-C38 building blocks of halichondrins and analogs thereof with limited or no purification or separation of the intermediates.

RELATED APPLICATIONS

The present application claims priority under 35 U.S.C. § 119(e) to U.S.provisional patent application, U.S. Ser. No. 62/155,067, filed Apr. 30,2015, which is incorporated herein by reference.

BACKGROUND OF THE INVENTION

The halichondrins are polyether macrolides, originally isolated from themarine sponge Halichondria okadai by Uemura, Hirata, and coworkers. Dueto their intriguing structural architecture and extraordinary in vitroand in vivo anti-proliferative activity, the halichondrins have receivedmuch attention from the scientific community. Synthetic methods thatstreamline the preparation of these natural products or relatedderivatives are important given the structural complexity of thehalichondrin backbone. A highly convergent approach has been adopted tosynthesize halichondrins and analogs thereof. Because of its high degreeof convergence, one can expect a high overall efficiency for the longestlinear synthetic sequence. Interestingly, the key two couplings havebeen achieved efficiently with Ni/Cr-mediated reactions: one between thebuilding blocks C20-C38 and C1-C19 to synthesize the macrolide; andanother between a vinyl iodide and an aldehyde to synthesize thebuilding block C1-C19. The structure of Halichondrin B is shown below,with carbon atoms numbered.

Chromium-mediated couplings of organic halides/triflates with aldehydesbelong to a class of 1,2-carbonyl addition reactions. In this process,the active nucleophiles RCrX₃ are generated from halides/triflates insitu. Depending on the mode of activation, chromium-mediated couplingsare divided into three sub-groups: (1) Ni/Cr-mediated alkenylation,alkynylation, and arylation, (2) Co or Fe/Cr-mediated alkylation,2-haloallyl-ation and propargylation, and (3) Cr-mediated allylation andpropargylation (See, e.g., Saccomano, N. A. in Comprehensive OrganicSynthesis; Trost, B. M., Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol.1, p 173).

Ni/Cr-mediated couplings of alkenyl halides/triflates with aldehydeswere originally reported by Takai, Hiyama, Nozaki, and coworkers in1983. Since then, it has been shown that the coupling is initiated by acatalytic amount of NiCl₂ as a contaminant in the with CrCl₂. It is nowgenerally accepted that this coupling involves: (1) oxidative additionof Ni(0), formed from NiCl₂ via reduction with CrCl₂ in situ, to analkenyl halide/triflate to form an alkenyl Ni(II)-species, (2)transmetallation of the resultant Ni(II)-species to Cr(II)Cl₂ to formalkenyl Cr(III)-species, and (3) carbonyl addition of the resultantCr(III)-species to an aldehyde to form the product Cr(III)-alkoxide(FIG. 5). Chemistry has been developed to achieve this coupling in acatalytic and asymmetric manner.

Due to the important biological activities of halichondrins, it isvaluable to develop a unified and practical synthesis of the C1-C19building block, as well as C20-C38 building blocks, to allow easy accessto halichondrins (e.g., halichondrin A, B, C; norhalichondrin A, B, C;homohalichondrin A, B, C; eribulin), and analogs thereof.

SUMMARY OF THE INVENTION

As part of the ongoing research effort aimed at a unified totalsynthesis of members of the halichondrin class of marine naturalproducts, an efficient synthesis of the C1-C19 building block has beendeveloped (FIG. 4), and is provided herein. Furthermore, a practical andefficient synthesis of C20-C38 building blocks has also been developedand is provided herein. In the recently reported total synthesis ofhalichondrin A (Ueda et al., J. Am. Chem. Soc., 2014, 136, 5171), theC1-C19 building block is joined with the C20-C38 building block tosynthesize halichondrin A, B, and C, as well as their analogs (e.g.,norhalichondrin A, B, C; homohalichondrin A, B, C; eribulin).

In one aspect, the present invention provides chromium-mediated couplingreactions which can be applied to the synthesis of halichondrins as wellas other molecules. In one aspect, the present invention provides amethod of preparing a compound of Formula (I):

or a salt thereof, the method comprises coupling a compound of Formula(i):

or a salt thereof, with an aldehyde of Formula (ii):

in the presence of a chromium catalyst and optionally one or morecatalysts (e.g., a nickel catalyst and a zirconium catalyst), whereinR¹, R², R³, R⁴, and R⁷ are as defined herein. The provided couplingmethod effectively furnishes the coupling a wide range of halo-enone,halo-enone ketal, halo-acetylenic ketone, or halo-acetylenic ketalsubstrates and an aldehyde. Since a hydroxyl group is generated in thecoupling product, an R- or S-isomer can be introduced in the chiralcenter. In some embodiments, the provided coupling method is a catalyticasymmetric coupling between the compound of Formula (i) and the aldehydeof Formula (ii). The chromium catalyst and one or more catalysts in thecoupling can provide efficient asymmetric induction, geometricalisomerization, and coupling rate. In certain embodiments, the couplingreaction is catalyzed by a chromoium complex. In certain embodiments,the coupling reaction is catalyzed by a chromoium complex and one ormore catalysts. In certain embodiments, the coupling reaction iscatalyzed by a chromoium complex and a zirconium complex. In certainembodiments, the coupling reaction is catalyzed by a chromium complexand a nickel complex. In certain embodiments, the coupling reaction iscatalyzed by a combination of a chromoium complex, a nickel complex, anda zirconium complex. In certain embodiments, the coupling reaction iscatalyzed by a chromoium complex, wherein the chromoium complexcomprises a chiral ligand. In certain embodiments, the coupling reactionis catalyzed by a chromoium complex and one or more catalysts, whereinthe chromoium complex comprises a chiral ligand. In certain embodiments,the coupling reaction is catalyzed by a chromoium complex and azirconium complex, wherein the chromoium complex comprises a chiralligand. In certain embodiments, the coupling reaction is catalyzed by achromium complex and a nickel complex, wherein the chromoium complexcomprises a chiral ligand. In certain embodiments, the coupling reactionis catalyzed by a combination of a chromoium complex, a nickel complex,and a zirconium complex, wherein the chromoium complex comprises achiral ligand.

In certain embodiments, the provided coupling method is stereoselectivein installing a chiral center having a hydroxyl group. In certainembodiments, the compound of Formula (i) is a halo-enone or halo-enoneketal of Formula (i-a):

or a salt thereof, and the asymmetric coupling product is of Formula(I-a):

or salt thereof. In certain embodiments, the compound of Formula (i) isa halo-acetylenic ketone or halo-acetylenic ketal of Formula (i-b):

or a salt thereof, and the asymmetric coupling product is of Formula(I-b):

or a salt thereof.

In certain embodiments, the provided coupling method is selective forhalo-enone, halo-enone ketal, halo-acetylenic enone, and halo-acetylenicketal, over vinyl halide and a halide attached to a sp³ hybridizedcarbon. A vinyl halide or a halide attached to a sp³ hybridized carboncan remain intact during the coupling reaction between a halo-enone,halo-enone ketal, halo-acetylenic enone, or halo-acetylenic ketal, withan aldehyde of Formula (ii). The vinyl halide moiety can be a part ofthe compound of Formula (i), the aldehyde of Formula (ii), or anothercompound in the coupling reaction mixture. In certain embodiments, theprovided coupling method is selective for halo-enone, halo-enone ketal,halo-acetylenic enone, and halo-acetylenic ketal, over vinyl iodide andchloride or iodide attached to a sp³ hybridized carbon. In certainembodiments, the provided coupling method is selective forhalo-acetylenic ketone or halo-acetylenic ketal over vinyl iodide or aiodide and chloride attached to a sp³ hybridized carbon. The providedcoupling methods are applicable to synthesizing the C1-C19 buildingblock of halichondrins and analogs thereof as well as other compounds.The provided coupling methods are also applicable to the preparation ofC20-C38 building blocks of halichondrins and analogs thereof.Furthermore, the provided coupling methods are useful in joining C1-C19building blocks with C20-C38 building blocks, as well as joining theright half and left half of halichondrins and analogs thereof. Forexamples, see Schemes T1-T4.

In certain embodiments, the compound of Formula (i) is of Formula(i-a-3):

or a salt thereof;and the aldehyde of Formula (ii) is of Formula (ii-a):

or a salt thereof;and the compound of Formula (I) is of Formula (I-a-3):

or a salt thereof,wherein R^(4a), R^(4b), R^(4c), R^(1a), and R^(1d) are as definedherein.

In certain embodiments, the compound of Formula (i) is of Formula(i-b-5):

or a salt thereof, andand the aldehyde of Formula (ii) is of Formula (ii-a):

or a salt thereof, andthe compound of Formula (I) is of Formula (I-b-5):

or a salt thereof,wherein R^(4a), R^(4b), R^(4c), R^(1a) and R^(1d) are as defined herein.

In another aspect, the present invention provides the synthesis of theC1-C19 building block of halichondrin A:

or a salt thereof, wherein R^(4a), R^(1a), R^(1d), R¹⁰, and R¹¹ are asdefined herein.

In another aspect, the present invention provides the synthesis of theC1-C19 building block of halichondrin B:

or a salt thereof, wherein R^(4a), R^(1a), and R^(1d) are as definedherein.

In another aspect, the present invention provides the synthesis of theC1-C19 building block of halichondrin C:

or a salt thereof, wherein R^(4a), R^(1a), R^(1d) and R¹⁰ are as definedherein.

In another aspect, the present invention provides methods of preparingC20-C38 building blocks of halichondrins (e.g., halichondrin A, B, C;norhalichondrin A, B, C; homohalichondrin A, B, C; eribulin), such ascompounds of Formula (III-1):

In certain embodiments, a C20-C38 building block is a compound ofFormula (III-11). Provided herein are methods of preparing a compound ofFormula (III-11):

In another aspect, the prevent invention provides compounds which areuseful intermediates in the preparation of halichondrins and buildingblocks described herein.

The details of certain embodiments of the invention are set forth in theDetailed Description of Certain Embodiments of the Invention, asdescribed below. Other features, objects, and advantages of theinvention will be apparent from the Claims.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows HPLC analysis of (R)-XS-27′ (top) and rac-XS-27′ (bottom)(see Example 1).

FIG. 2 shows an exemplary ion-exchange resin device consisting of apump, reaction flask, and ion-exchange columns.

FIG. 3 shows the crystal structure of XS-38.

FIG. 4 shows a novel approach to the synthesis of the C1-C19 buildingblock in the halichondrins.

FIG. 5 shows catalytic Ni/Cr-mediated coupling reaction. FIG. 5A:overall transformation; FIG. 5B: Ni- and Cr-catalytic cycles. Zr(cp)₂Cl₂or TMS-Cl is used to dissociate the product from Cr-species, toregenerate the Cr-catalyst.

FIG. 6 shows three coupling examples reported in the literature (Aicher,T. D.; Buszek, K. R.; Fang, F. G.; Forsyth, C. J.; Jung, S. H.; Kishi,Y.; Scola, P. M. Tetrahedron Lett. 1992, 33, 1549; Chen, C.; Tagami, K.;Kishi, Y. J. Org. Chem. 1995, 60, 5386. (c) Namba, K.; Kishi, Y. Org.Lett. 2004, 6, 5031; Guo, H.; Dong, C.-G.; Kim, D.-S.; Urabe, D.; Wang,J.; Kim, J. T.; Liu, X.; Sasaki, T.; Kishi, Y. J. Am. Chem. Soc. 2009,131, 15387; Knochel, P.; Rao, C. J. Tetrahedron, 1993, 49, 29; Kress, M.H.; Rucl, R.; Miller, W. H.; Kishi, Y. Tetrahedron Lett. 1993, 34,6003).

FIG. 7 shows model coupling reactions used to assess couplingefficiency. Coupling condition X-A: 10 mol % Cr-complex prepared fromsulfonamide X-12 and 1 mol % nickel complex X-13a; Coupling conditionX-B: 10 mol % Cr-complex prepared from sulfonamide X-12 and 0.05 mol %nickel complex X-13b; Yields are based on chromatographically isolatedproduct.

FIG. 8 shows examples tested for the coupling of di-substitutedtrans-β-bromoenones with aldehydes. Coupling condition: 10 mol %Cr-catalyst, prepared from sulfonamide X-12, 0.05 mol % Ni-complexX-13b, Zr(cp)₂Cl₂ (1.5 eq), LiCl (2 eq), and Mn (2 eq) in McCN ([C] 0.4M) at room temperature for 3 hours; Yield: based on chromatographicallyisolated products.

FIG. 9 shows attempted coupling with other types of β-bromo-enones. Forcoupling conditions, please see FIG. 8.

FIG. 10 shows two examples relevant to the synthesis of the C1-C19building block of halichondrins. The first example shows that aselective activation/coupling is possible with the use of a selectiveactivator in the Cr-mediated coupling; namely, cobalt- and iron-saltsare known to activate saturated halides, but not vinyl halides (Guo, H.;Dong, C.-G.; Kim, D.-S.; Urabe, D.; Wang, J.; Kim, J. T.; Liu, X.;Sasaki, T.; Kishi, Y. J. Am. Chem. Soc. 2009, 131, 15387; Takai, K.;Nitta, K.; Fujimura, O.; Utimoto, K. J. Org. Chem. 1989, 54, 4732; Wan,Z.-K.; Choi, H.-w.; Kang, F.-A.; Nakajima, K.; Demeke, D.; Kishi, Y.Org. Lett. 2002, 4, 4431). The second example shows that selectiveactivation of iodoacetylene in the Ni/Cr-mediated reaction is possiblewithout disturbing the vinyl iodide present in the electrophile (Ueda,A.; Yamamoto, A.; Kato, D.; Kishi, Y. J. Am. Chem. Soc. 2014, 136,5171).

FIG. 11 shows a competition experiment of trans-β-bromoenone X-9b overvinyl iodides X-31a˜c. Coupling condition: nucleophile: a 1:1 mixture ofX-9b and X-31a, b, or c. Reagents: 10 mol % Cr-catalyst, prepared fromsulfonamide X-12, 0.05 mol % Ni-complex X-13a or X-13b, Zr(cp)₂Cl₂ (1.5eq), LiCl (2 eq), and Mn (2 eq) in MeCN ([C] 0.4 M) at room temperaturefor 3 hours. The product ratio was estimated from ¹H NMR analysis ofcrude coupling products.

FIG. 12 shows an exemplary synthesis of poly-halogenated nucleophileX-34.

FIG. 13 shows Ni/Cr-mediated coupling of X-34 with X-35, with use ofpolyether-type phenanthrene.NiCl₂ complex X-37c. Coupling condition: 10mol % Cr-catalyst, prepared from sulfonamide X-12, 0.05 mol % Ni-complexX-37c, Zr(cp)₂Cl₂ (1.5 eq), LiCl (2 eq), and Mn (2 eq) in MeCN ([C] 0.4M) at room temperature for 3 hours. Yield: chromatographically isolatedyield in 7.1 g aldehyde scale.

FIG. 14 shows examples tested for the coupling of poly-halogenatednucleophile X-34 with various aldehydes. Coupling condition: 10 mol %Cr-catalyst, prepared from sulfonamide X-12, 0.05 mol % Ni-complexX-37c, Zr(cp)₂Cl₂ (1.5 eq), LiCl (2 eq), and Mn (2 eq) in MeCN ([C] 0.4M) at room temperature for 3 hours; Yield: based on chromatographicallyisolated products.

FIG. 15 shows the completion of synthesis of the C1-C19 building blockX-46 of halichondrin Bs. Yield: chromatographically isolated yield in11.4 g scale of coupling product X-36.

FIG. 16 shows polymer-bound guanidine and PPTS used forion-exchange-resin based device.

FIG. 17 shows a summary of the exemplary synthesis of the right-half ofhalichondrin A.

FIG. 18 shows structures of halichondrins A, B, and C.

FIG. 19 shows a summary of the synthesis of the right half ofhalichondrin A and requisite C1-C19 building blocks (BBs) ofhalichondrins A-C.

FIG. 20 shows a proposed one-step synthesis of acetylenic ketonesY-15a,b via selective activation/coupling of halo-acetylenic ketonesY-16a,b.

FIG. 21 shows substrates, sulfonamide, and Ni-catalyst used for themodel study.

FIG. 22 shows an exemplary synthesis of nucleophiles Y-24a,b.

FIG. 23 shows exemplary sulfonamides.

FIG. 24 shows (Ni)/Cr-Mediated couplings. Coupling condition:Cr-catalyst prepared from (R)-Y-21: 20 mol %; Ni-catalyst Y-22b (0.05mol %) or no added Ni-catalyst; TES-Cl (2.5 eq); LiCl (4 eq); Mn (4 eq);EtCN ([C] 0.4 M); RT; Yields are based on chromatographically isolatedproduct.

FIG. 25 shows an exemplary synthesis of C1-C19 building blocks (BBs) inthe halichondrin A and C series.

FIG. 26 shows an exemplary synthesis of C1-C19 BBs in the halichondrin Bseries.

FIG. 27 shows an exemplary synthesis of C1-C19 building blocks fromcompound Y-11.

FIG. 28 shows an example of a transformation that can be used to preparehalichondrins A-C and norhalichondrins A-C. This transformation isachieved in four steps (i.e., 1. TBAF, 2. DBU, 3. DDQ, and PPTS). In thehalichondrin-A and -C series, after this transformation, the protectinggroups at C11 at C12 can be removed to yield the natural product. Theenone-to-halichondrin transformation can be carried out with severalcombinations of the protecting groups for the hydroxyl groups,including, for example, C35-TES (triethylsilyl), C41-MPM(4-methoxybenzyl), C48-TES, C51-TES, C53-TBS (tert-butyl dimethylsilyl),and C54-TBS in the halichondrin-B series; C35-TES, C41-MPM, C48-TES, andC50-TES in the norhalichondrin-B series. In FIG. 28, X is an oxygenprotecting group.

FIG. 29 shows an improved protecting group strategy for theenone-to-halichondrin transformation and enone-to-norhalichondrintransformations in FIG. 28. Use of a TES-protecting group for the C35-and C48-hydroxyl groups allows the use of a TBS-protecting group for theC41-hydroxyl group. With this change, the enone-to-halichondrintransformation can be completed in two steps, instead of four steps.Improved combinations of protecting groups for this synthetic sequenceinclude: C35-TES, C41-TBS, C48-TES, C51-TES, C53-TBS, and C54-TBS in thehalichondrin-B series; C35-TES, C41-TBS, C48-TES, and C50-TES in thenorhalichondrin-B series. This combination of protecting groups can beused to prepare halichondrins A-C as well as norhalichondrins A-C.

FIG. 30 shows how the two-step enone-to-halichondrin transformation canbe applied to the synthesis of the norhalichondrin series (e.g.,norhalichondrin C as shown).

DEFINITIONS Chemical Definitions

Definitions of specific functional groups and chemical terms aredescribed in more detail below. The chemical elements are identified inaccordance with the Periodic Table of the Elements, CAS version,Handbook of Chemistry and Physics, 75^(th) Ed., inside cover, andspecific functional groups are generally defined as described therein.Additionally, general principles of organic chemistry, as well asspecific functional moieties and reactivity, are described in OrganicChemistry, Thomas Sorrell, University Science Books, Sausalito, 1999;Smith and March March's Advanced Organic Chemistry, 5^(th) Edition, JohnWiley & Sons, Inc., New York, 2001; Larock, Comprehensive OrganicTransformations, VCH Publishers, Inc., New York, 1989; and Carruthers,Some Modern Methods of Organic Synthesis, 3^(rd) Edition, CambridgeUniversity Press, Cambridge, 1987.

Compounds described herein can comprise one or more asymmetric centers,and thus can exist in various stereoisomeric forms, e.g., enantiomersand/or diastereomers. For example, the compounds described herein can bein the form of an individual enantiomer, diastereomer or geometricisomer, or can be in the form of a mixture of stereoisomers, includingracemic mixtures and mixtures enriched in one or more stereoisomer.Isomers can be isolated from mixtures by methods known to those skilledin the art, including chiral high pressure liquid chromatography (HPLC)and the formation and crystallization of chiral salts; or preferredisomers can be prepared by asymmetric syntheses. See, for example,Jacques et al., Enantiomers, Racemates and Resolutions (WileyInterscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977);Eliel, E. L. Stereochemistry of Carbon Compounds (McGraw-Hill, NY,1962); and Wilen, S. H. Tables of Resolving Agents and OpticalResolutions p. 268 (E. L. Eliel, Ed., Univ. of Notre Dame Press, NotreDame, Ind. 1972). The disclosure additionally encompasses compounds asindividual isomers substantially free of other isomers, andalternatively, as mixtures of various isomers.

The term “heteroatom” refers to an atom that is not hydrogen or carbon.In certain embodiments, the heteroatom is nitrogen. In certainembodiments, the heteroatom is oxygen. In certain embodiments, theheteroatom is sulfur.

When a range of values is listed, it is intended to encompass each valueand sub-range within the range. For example “C₁₋₆ alkyl” is intended toencompass, C₁, C₂, C₃, C₄, C₅, C₆, C₁₋₆, C₁₋₅, C₁₋₄, C₁₋₃, C₁₋₂, C₂₋₆,C₂₋₅, C₂₋₄, C₂₋₃, C₃₋₆, C₃₋₅, C₃₋₄, C₄₋₆, C₄₋₅, and C₅₋₆ alkyl.

The term “aliphatic” refers to alkyl, alkenyl, alkynyl, and carbocyclicgroups. Likewise, the term “heteroaliphatic” refers to heteroalkyl,heteroalkenyl, heteroalkynyl, and heterocyclic groups.

The term “alkyl” refers to a radical of a straight-chain or branchedsaturated hydrocarbon group having from 1 to 10 carbon atoms (“C₁₋₁₀alkyl”). In some embodiments, an alkyl group has 1 to 9 carbon atoms(“C₁₋₉ alkyl”). In some embodiments, an alkyl group has 1 to 8 carbonatoms (“C₁₋₈ alkyl”). In some embodiments, an alkyl group has 1 to 7carbon atoms (“C₁₋₇ alkyl”). In some embodiments, an alkyl group has 1to 6 carbon atoms (“C₁₋₆ alkyl”). In some embodiments, an alkyl grouphas 1 to 5 carbon atoms (“C₁₋₅ alkyl”). In some embodiments, an alkylgroup has 1 to 4 carbon atoms (“C₁₋₄ alkyl”). In some embodiments, analkyl group has 1 to 3 carbon atoms (“C₁₋₃ alkyl”). In some embodiments,an alkyl group has 1 to 2 carbon atoms (“C₁₋₂ alkyl”). In someembodiments, an alkyl group has 1 carbon atom (“C₁ alkyl”). In someembodiments, an alkyl group has 2 to 6 carbon atoms (“C₂₋₆ alkyl”).Examples of C₁₋₆ alkyl groups include methyl (C₁), ethyl (C₂), n-propyl(C₃), isopropyl (C₃), n-butyl (C₄), tert-butyl (C₄), sec-butyl (C₄),iso-butyl (C₄), n-pentyl (C₅), 3-pentanyl (C₅), amyl (C₅), neopentyl(C₅), 3-methyl-2-butanyl (C₅), tertiary amyl (C₅), and n-hexyl (C₆).Additional examples of alkyl groups include n-heptyl (C₇), n-octyl (C₈)and the like. Unless otherwise specified, each instance of an alkylgroup is independently unsubstituted (an “unsubstituted alkyl”) orsubstituted (a “substituted alkyl”) with one or more substituents. Incertain embodiments, the alkyl group is an unsubstituted C₁₋₁₀ alkyl(e.g., —CH₃). In certain embodiments, the alkyl group is a substitutedC₁₋₁₀ alkyl.

The term “haloalkyl” is a substituted alkyl group, wherein one or moreof the hydrogen atoms are independently replaced by a halogen, e.g.,fluoro, bromo, chloro, or iodo. “Perhaloalkyl” is a subset of haloalkyl,and refers to an alkyl group wherein all of the hydrogen atoms areindependently replaced by a halogen, e.g., fluoro, bromo, chloro, oriodo. In some embodiments, the haloalkyl moiety has 1 to 8 carbon atoms(“C₁₋₈ haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 6carbon atoms (“C₁₋₆ haloalkyl”). In some embodiments, the haloalkylmoiety has 1 to 4 carbon atoms (“C₁₋₄ haloalkyl”). In some embodiments,the haloalkyl moiety has 1 to 3 carbon atoms (“C₁₋₃ haloalkyl”). In someembodiments, the haloalkyl moiety has 1 to 2 carbon atoms (“C₁₋₂haloalkyl”). In some embodiments, all of the haloalkyl hydrogen atomsare replaced with fluoro to provide a perfluoroalkyl group. In someembodiments, all of the haloalkyl hydrogen atoms are replaced withchloro to provide a “perchloroalkyl” group. Examples of haloalkyl groupsinclude —CHF2, —CH2F, —CF₃, —CH2CF3, —CF₂CF₃, —CF₂CF₂CF₃, —CCl₃, —CFCl₂,—CF₂Cl, and the like.

The term “heteroalkyl” refers to an alkyl group, which further includesat least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected fromoxygen, nitrogen, or sulfur within (i.e., inserted between adjacentcarbon atoms of) and/or placed at one or more terminal position(s) ofthe parent chain. In certain embodiments, a heteroalkyl group refers toa saturated group having from 1 to 10 carbon atoms and 1 or moreheteroatoms within the parent chain (“heteroC₁₋₁₀ alkyl”). In someembodiments, a heteroalkyl group is a saturated group having 1 to 9carbon atoms and 1 or more heteroatoms within the parent chain(“heteroC₁₋₉ alkyl”). In some embodiments, a heteroalkyl group is asaturated group having 1 to 8 carbon atoms and 1 or more heteroatomswithin the parent chain (“heteroC₁₋₈ alkyl”). In some embodiments, aheteroalkyl group is a saturated group having 1 to 7 carbon atoms and 1or more heteroatoms within the parent chain (“heteroC₁₋₇ alkyl”). Insome embodiments, a heteroalkyl group is a saturated group having 1 to 6carbon atoms and 1 or more heteroatoms within the parent chain(“heteroC₁₋₆ alkyl”). In some embodiments, a heteroalkyl group is asaturated group having 1 to 5 carbon atoms and 1 or 2 heteroatoms withinthe parent chain (“heteroC₁₋₅ alkyl”). In some embodiments, aheteroalkyl group is a saturated group having 1 to 4 carbon atoms andfor 2 heteroatoms within the parent chain (“heteroC₁₋₄ alkyl”). In someembodiments, a heteroalkyl group is a saturated group having 1 to 3carbon atoms and 1 heteroatom within the parent chain (“heteroC₁₋₃alkyl”). In some embodiments, a heteroalkyl group is a saturated grouphaving 1 to 2 carbon atoms and 1 heteroatom within the parent chain(“heteroC₁₋₂ alkyl”). In some embodiments, a heteroalkyl group is asaturated group having 1 carbon atom and 1 heteroatom (“heteroC₁alkyl”). In some embodiments, a heteroalkyl group is a saturated grouphaving 2 to 6 carbon atoms and 1 or 2 heteroatoms within the parentchain (“heteroC₂₋₆ alkyl”). Unless otherwise specified, each instance ofa heteroalkyl group is independently unsubstituted (an “unsubstitutedheteroalkyl”) or substituted (a “substituted heteroalkyl”) with one ormore substituents. In certain embodiments, the heteroalkyl group is anunsubstituted heteroC₁₋₁₀ alkyl. In certain embodiments, the heteroalkylgroup is a substituted heteroC₁₋₁₀ alkyl.

The term “alkenyl” refers to a radical of a straight-chain or branchedhydrocarbon group having from 2 to 10 carbon atoms and one or morecarbon-carbon double bonds (e.g., 1, 2, 3, or 4 double bonds). In someembodiments, an alkenyl group has 2 to 9 carbon atoms (“C₂₋₉ alkenyl”).In some embodiments, an alkenyl group has 2 to 8 carbon atoms (“C₂₋₈alkenyl”). In some embodiments, an alkenyl group has 2 to 7 carbon atoms(“C₂₋₇ alkenyl”). In some embodiments, an alkenyl group has 2 to 6carbon atoms (“C₂₋₆ alkenyl”). In some embodiments, an alkenyl group has2 to 5 carbon atoms (“C₂₋₅ alkenyl”). In some embodiments, an alkenylgroup has 2 to 4 carbon atoms (“C₂₋₄ alkenyl”). In some embodiments, analkenyl group has 2 to 3 carbon atoms (“C₂₋₃ alkenyl”). In someembodiments, an alkenyl group has 2 carbon atoms (“C₂ alkenyl”). The oneor more carbon-carbon double bonds can be internal (such as in2-butenyl) or terminal (such as in 1-butenyl). Examples of C₂₋₄ alkenylgroups include ethenyl (C₂), 1-propenyl (C₃), 2-propenyl (C₃), 1-butenyl(C₄), 2-butenyl (C₄), butadienyl (C₄), and the like. Examples of C₂₋₆alkenyl groups include the aforementioned C₂₋₄ alkenyl groups as well aspentenyl (C₅), pentadienyl (C₅), hexenyl (C₆), and the like. Additionalexamples of alkenyl include heptenyl (C₇), octenyl (C₈), octatrienyl(C₈), and the like. Unless otherwise specified, each instance of analkenyl group is independently unsubstituted (an “unsubstitutedalkenyl”) or substituted (a “substituted alkenyl”) with one or moresubstituents. In certain embodiments, the alkenyl group is anunsubstituted C₂₋₁₀ alkenyl. In certain embodiments, the alkenyl groupis a substituted C₂₋₁₀ alkenyl. In an alkenyl group, a C═C double bondfor which the stereochemistry is unspecified (e.g., —CH═CHCH₃ or

may be an (E)- or (Z)-double bond.

The term “heteroalkenyl” refers to an alkenyl group, which furtherincludes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms)selected from oxygen, nitrogen, or sulfur within (i.e., inserted betweenadjacent carbon atoms of) and/or placed at one or more terminalposition(s) of the parent chain. In certain embodiments, a heteroalkenylgroup refers to a group having from 2 to 10 carbon atoms, at least onedouble bond, and 1 or more heteroatoms within the parent chain(“heteroC₂₋₁₀ alkenyl”). In some embodiments, a heteroalkenyl group has2 to 9 carbon atoms at least one double bond, and 1 or more heteroatomswithin the parent chain (“heteroC₂₋₉ alkenyl”). In some embodiments, aheteroalkenyl group has 2 to 8 carbon atoms, at least one double bond,and 1 or more heteroatoms within the parent chain (“heteroC₂₋₈alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 7 carbonatoms, at least one double bond, and 1 or more heteroatoms within theparent chain (“heteroC₂₋₇ alkenyl”). In some embodiments, aheteroalkenyl group has 2 to 6 carbon atoms, at least one double bond,and 1 or more heteroatoms within the parent chain (“heteroC₂₋₆alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 5 carbonatoms, at least one double bond, and 1 or 2 heteroatoms within theparent chain (“heteroC₂₋₅ alkenyl”). In some embodiments, aheteroalkenyl group has 2 to 4 carbon atoms, at least one double bond,and for 2 heteroatoms within the parent chain (“heteroC₂₋₄ alkenyl”). Insome embodiments, a heteroalkenyl group has 2 to 3 carbon atoms, atleast one double bond, and 1 heteroatom within the parent chain(“heteroC₂₋₃ alkenyl”). In some embodiments, a heteroalkenyl group has 2to 6 carbon atoms, at least one double bond, and 1 or 2 heteroatomswithin the parent chain (“heteroC₂₋₆ alkenyl”). Unless otherwisespecified, each instance of a heteroalkenyl group is independentlyunsubstituted (an “unsubstituted heteroalkenyl”) or substituted (a“substituted heteroalkenyl”) with one or more substituents. In certainembodiments, the heteroalkenyl group is an unsubstituted heteroC₂₋₁₀alkenyl. In certain embodiments, the heteroalkenyl group is asubstituted heteroC₂₋₁₀ alkenyl.

The term “alkynyl” refers to a radical of a straight-chain or branchedhydrocarbon group having from 2 to 10 carbon atoms and one or morecarbon-carbon triple bonds (e.g., 1, 2, 3, or 4 triple bonds) (“C₂₋₁₀alkynyl”). In some embodiments, an alkynyl group has 2 to 9 carbon atoms(“C₂₋₉ alkynyl”). In some embodiments, an alkynyl group has 2 to 8carbon atoms (“C₂₋₈ alkynyl”). In some embodiments, an alkynyl group has2 to 7 carbon atoms (“C₂₋₇ alkynyl”). In some embodiments, an alkynylgroup has 2 to 6 carbon atoms (“C₂₋₆ alkynyl”). In some embodiments, analkynyl group has 2 to 5 carbon atoms (“C₂₋₅ alkynyl”). In someembodiments, an alkynyl group has 2 to 4 carbon atoms (“C₂₋₄ alkynyl”).In some embodiments, an alkynyl group has 2 to 3 carbon atoms (“C₂₋₃alkynyl”). In some embodiments, an alkynyl group has 2 carbon atoms (“C₂alkynyl”). The one or more carbon-carbon triple bonds can be internal(such as in 2-butynyl) or terminal (such as in 1-butynyl). Examples ofC₂₋₄ alkynyl groups include, without limitation, ethynyl (C₂),1-propynyl (C₃), 2-propynyl (C₃), 1-butynyl (C₄), 2-butynyl (C₄), andthe like. Examples of C₂₋₆ alkenyl groups include the aforementionedC₂₋₄ alkynyl groups as well as pentynyl (C₅), hexynyl (C₆), and thelike. Additional examples of alkynyl include heptynyl (C₇), octynyl(C₈), and the like. Unless otherwise specified, each instance of analkynyl group is independently unsubstituted (an “unsubstitutedalkynyl”) or substituted (a “substituted alkynyl”) with one or moresubstituents. In certain embodiments, the alkynyl group is anunsubstituted C₂₋₁₀ alkynyl. In certain embodiments, the alkynyl groupis a substituted C₂₋₁₀ alkynyl.

The term “heteroalkynyl” refers to an alkynyl group, which furtherincludes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms)selected from oxygen, nitrogen, or sulfur within (i.e., inserted betweenadjacent carbon atoms of) and/or placed at one or more terminalposition(s) of the parent chain. In certain embodiments, a heteroalkynylgroup refers to a group having from 2 to 10 carbon atoms, at least onetriple bond, and 1 or more heteroatoms within the parent chain(“heteroC₂₋₁₀ alkynyl”). In some embodiments, a heteroalkynyl group has2 to 9 carbon atoms, at least one triple bond, and 1 or more heteroatomswithin the parent chain (“heteroC₂₋₉ alkynyl”). In some embodiments, aheteroalkynyl group has 2 to 8 carbon atoms, at least one triple bond,and 1 or more heteroatoms within the parent chain (“heteroC₂₋₈alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 7 carbonatoms, at least one triple bond, and 1 or more heteroatoms within theparent chain (“heteroC₂₋₇ alkynyl”). In some embodiments, aheteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond,and 1 or more heteroatoms within the parent chain (“heteroC₂₋₆alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 5 carbonatoms, at least one triple bond, and 1 or 2 heteroatoms within theparent chain (“heteroC₂₋₅ alkynyl”). In some embodiments, aheteroalkynyl group has 2 to 4 carbon atoms, at least one triple bond,and for 2 heteroatoms within the parent chain (“heteroC₂₋₄ alkynyl”). Insome embodiments, a heteroalkynyl group has 2 to 3 carbon atoms, atleast one triple bond, and 1 heteroatom within the parent chain(“heteroC₂₋₃ alkynyl”). In some embodiments, a heteroalkynyl group has 2to 6 carbon atoms, at least one triple bond, and 1 or 2 heteroatomswithin the parent chain (“heteroC₂₋₆ alkynyl”). Unless otherwisespecified, each instance of a heteroalkynyl group is independentlyunsubstituted (an “unsubstituted heteroalkynyl”) or substituted (a“substituted heteroalkynyl”) with one or more substituents. In certainembodiments, the heteroalkynyl group is an unsubstituted heteroC₂₋₁₀alkynyl. In certain embodiments, the heteroalkynyl group is asubstituted heteroC₂₋₁₀ alkynyl.

The term “carbocyclyl” or “carbocyclic” refers to a radical of anon-aromatic cyclic hydrocarbon group having from 3 to 14 ring carbonatoms (“C₃₋₁₄ carbocyclyl”) and zero heteroatoms in the non-aromaticring system. In some embodiments, a carbocyclyl group has 3 to 10 ringcarbon atoms (“C₃₋₁₀ carbocyclyl”). In some embodiments, a carbocyclylgroup has 3 to 8 ring carbon atoms (“C₃₋₈ carbocyclyl”). In someembodiments, a carbocyclyl group has 3 to 7 ring carbon atoms (“C₃₋₇carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 6 ringcarbon atoms (“C₃₋₆ carbocyclyl”). In some embodiments, a carbocyclylgroup has 4 to 6 ring carbon atoms (“C₄₋₆ carbocyclyl”). In someembodiments, a carbocyclyl group has 5 to 6 ring carbon atoms (“C₅₋₆carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 10 ringcarbon atoms (“C₅₋₁₀ carbocyclyl”). Exemplary C₃₋₆ carbocyclyl groupsinclude, without limitation, cyclopropyl (C₃), cyclopropenyl (C₃),cyclobutyl (C₄), cyclobutenyl (C₄), cyclopentyl (C₅), cyclopentenyl(C₅), cyclohexyl (C₆), cyclohexenyl (C₆), cyclohexadienyl (C₆), and thelike. Exemplary C₃₋₈ carbocyclyl groups include, without limitation, theaforementioned C₃₋₆ carbocyclyl groups as well as cycloheptyl (C₇),cycloheptenyl (C₇), cycloheptadienyl (C₇), cycloheptatrienyl (C₇),cyclooctyl (C₈), cyclooctenyl (C₈), bicyclo[2.2.1]heptanyl (C₇),bicyclo[2.2.2]octanyl (C₈), and the like. Exemplary C₃₋₁₀ carbocyclylgroups include, without limitation, the aforementioned C₃₋₈ carbocyclylgroups as well as cyclononyl (C₉), cyclononenyl (C₉), cyclodecyl (C₁₀),cyclodecenyl (C₁₀), octahydro-1H-indenyl (C₉), decahydronaphthalenyl(C₁₀), spiro[4.5]decanyl (C₁₀), and the like. As the foregoing examplesillustrate, in certain embodiments, the carbocyclyl group is eithermonocyclic (“monocyclic carbocyclyl”) or polycyclic (e.g., containing afused, bridged or Spiro ring system such as a bicyclic system (“bicycliccarbocyclyl”) or tricyclic system (“tricyclic carbocyclyl”)) and can besaturated or can contain one or more carbon-carbon double or triplebonds. “Carbocyclyl” also includes ring systems wherein the carbocyclylring, as defined above, is fused with one or more aryl or heteroarylgroups wherein the point of attachment is on the carbocyclyl ring, andin such instances, the number of carbons continue to designate thenumber of carbons in the carbocyclic ring system. Unless otherwisespecified, each instance of a carbocyclyl group is independentlyunsubstituted (an “unsubstituted carbocyclyl”) or substituted (a“substituted carbocyclyl”) with one or more substituents. In certainembodiments, the carbocyclyl group is an unsubstituted C₃₋₁₄carbocyclyl. In certain embodiments, the carbocyclyl group is asubstituted C₃₋₁₄ carbocyclyl.

In some embodiments, “carbocyclyl” is a monocyclic, saturatedcarbocyclyl group having from 3 to 14 ring carbon atoms (“C₃₋₁₄cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 10 ringcarbon atoms (“C₃₋₁₀ cycloalkyl”). In some embodiments, a cycloalkylgroup has 3 to 8 ring carbon atoms (“C₃₋₈ cycloalkyl”). In someembodiments, a cycloalkyl group has 3 to 6 ring carbon atoms (“C₃₋₆cycloalkyl”). In some embodiments, a cycloalkyl group has 4 to 6 ringcarbon atoms (“C₄₋₆ cycloalkyl”). In some embodiments, a cycloalkylgroup has 5 to 6 ring carbon atoms (“C₅₋₆ cycloalkyl”). In someembodiments, a cycloalkyl group has 5 to 10 ring carbon atoms (“C₅₋₁₀cycloalkyl”). Examples of C₅₋₆ cycloalkyl groups include cyclopentyl(C₅) and cyclohexyl (C₅). Examples of C₃₋₆ cycloalkyl groups include theaforementioned C₅₋₆ cycloalkyl groups as well as cyclopropyl (C₃) andcyclobutyl (C₄). Examples of C₃₋₈ cycloalkyl groups include theaforementioned C₃₋₆ cycloalkyl groups as well as cycloheptyl (C₇) andcyclooctyl (C₈). Unless otherwise specified, each instance of acycloalkyl group is independently unsubstituted (an “unsubstitutedcycloalkyl”) or substituted (a “substituted cycloalkyl”) with one ormore substituents. In certain embodiments, the cycloalkyl group is anunsubstituted C₃₋₁₄ cycloalkyl. In certain embodiments, the cycloalkylgroup is a substituted C₃₋₁₄ cycloalkyl.

The term “heterocyclyl” or “heterocyclic” refers to a radical of a 3- to14-membered non-aromatic ring system having ring carbon atoms and 1 to 4ring heteroatoms, wherein each heteroatom is independently selected fromnitrogen, oxygen, and sulfur (“3-14 membered heterocyclyl”). Inheterocyclyl groups that contain one or more nitrogen atoms, the pointof attachment can be a carbon or nitrogen atom, as valency permits. Aheterocyclyl group can either be monocyclic (“monocyclic heterocyclyl”)or polycyclic (e.g., a fused, bridged or Spiro ring system such as abicyclic system (“bicyclic heterocyclyl”) or tricyclic system(“tricyclic heterocyclyl”)), and can be saturated or can contain one ormore carbon carbon double or triple bonds. Heterocyclyl polycyclic ringsystems can include one or more heteroatoms in one or both rings.“Heterocyclyl” also includes ring systems wherein the heterocyclyl ring,as defined above, is fused with one or more carbocyclyl groups whereinthe point of attachment is either on the carbocyclyl or heterocyclylring, or ring systems wherein the heterocyclyl ring, as defined above,is fused with one or more aryl or heteroaryl groups, wherein the pointof attachment is on the heterocyclyl ring, and in such instances, thenumber of ring members continue to designate the number of ring membersin the heterocyclyl ring system. Unless otherwise specified, eachinstance of heterocyclyl is independently unsubstituted (an“unsubstituted heterocyclyl”) or substituted (a “substitutedheterocyclyl”) with one or more substituents. In certain embodiments,the heterocyclyl group is an unsubstituted 3-14 membered heterocyclyl.In certain embodiments, the heterocyclyl group is a substituted 3-14membered heterocyclyl.

In some embodiments, a heterocyclyl group is a 5-10 memberednon-aromatic ring system having ring carbon atoms and 1-4 ringheteroatoms, wherein each heteroatom is independently selected fromnitrogen, oxygen, and sulfur (“5-10 membered heterocyclyl”). In someembodiments, a heterocyclyl group is a 5-8 membered non-aromatic ringsystem having ring carbon atoms and 1-4 ring heteroatoms, wherein eachheteroatom is independently selected from nitrogen, oxygen, and sulfur(“5-8 membered heterocyclyl”). In some embodiments, a heterocyclyl groupis a 5-6 membered non-aromatic ring system having ring carbon atoms and1-4 ring heteroatoms, wherein each heteroatom is independently selectedfrom nitrogen, oxygen, and sulfur (“5-6 membered heterocyclyl”). In someembodiments, the 5-6 membered heterocyclyl has 1-3 ring heteroatomsselected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen,oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclylhas 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

Exemplary 3-membered heterocyclyl groups containing 1 heteroatominclude, without limitation, aziridinyl, oxiranyl, and thiiranyl.Exemplary 4-membered heterocyclyl groups containing 1 heteroatominclude, without limitation, azetidinyl, oxetanyl, and thietanyl.Exemplary 5-membered heterocyclyl groups containing 1 heteroatominclude, without limitation, tetrahydrofuranyl, dihydrofuranyl,tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl,and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groupscontaining 2 heteroatoms include, without limitation, dioxolanyl,oxathiolanyl and dithiolanyl. Exemplary 5-membered heterocyclyl groupscontaining 3 heteroatoms include, without limitation, triazolinyl,oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclylgroups containing 1 heteroatom include, without limitation, piperidinyl,tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-memberedheterocyclyl groups containing 2 heteroatoms include, withoutlimitation, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary6-membered heterocyclyl groups containing 2 heteroatoms include, withoutlimitation, triazinanyl. Exemplary 7-membered heterocyclyl groupscontaining 1 heteroatom include, without limitation, azepanyl, oxepanyland thiepanyl. Exemplary 8-membered heterocyclyl groups containing 1heteroatom include, without limitation, azocanyl, oxecanyl andthiocanyl. Exemplary bicyclic heterocyclyl groups include, withoutlimitation, indolinyl, isoindolinyl, dihydrobenzofuranyl,dihydrobenzothienyl, tetrahydrobenzothienyl, tetrahydrobenzofuranyl,tetrahydroindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl,decahydroquinolinyl, decahydroisoquinolinyl, octahydrochromenyl,octahydroisochromenyl, decahydronaphthyridinyl,decahydro-1,8-naphthyridinyl, octahydropyrrolo[3,2-b]pyrrole, indolinyl,phthalimidyl, naphthalimidyl, chromanyl, chromenyl,1H-benzo[e][1,4]diazepinyl, 1,4,5,7-tetrahydropyrano[3,4-b]pyrrolyl,5,6-dihydro-4H-furo[3,2-b]pyrrolyl, 6,7-dihydro-5H-furo[3,2-b]pyranyl,5,7-dihydro-4H-thieno[2,3-c]pyranyl,2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl, 2,3-dihydrofuro[2,3-b]pyridinyl,4,5,6,7-tetrahydro-1H-pyrrolo[2,3-b]pyridinyl,4,5,6,7-tetrahydrofuro[3,2-c]pyridinyl,4,5,6,7-tetrahydrothieno[3,2-b]pyridinyl,1,2,3,4-tetrahydro-1,6-naphthyridinyl, and the like.

The term “aryl” refers to a radical of a monocyclic or polycyclic (e.g.,bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or14 π electrons shared in a cyclic array) having 6-14 ring carbon atomsand zero heteroatoms provided in the aromatic ring system (“C₆₋₁₄aryl”). In some embodiments, an aryl group has 6 ring carbon atoms (“C₆aryl”; e.g., phenyl). In some embodiments, an aryl group has 10 ringcarbon atoms (“C₁₀ aryl”; e.g., naphthyl such as 1-naphthyl and2-naphthyl). In some embodiments, an aryl group has 14 ring carbon atoms(“C₁₄ aryl”; e.g., anthracyl). “Aryl” also includes ring systems whereinthe aryl ring, as defined above, is fused with one or more carbocyclylor heterocyclyl groups wherein the radical or point of attachment is onthe aryl ring, and in such instances, the number of carbon atomscontinue to designate the number of carbon atoms in the aryl ringsystem. Unless otherwise specified, each instance of an aryl group isindependently unsubstituted (an “unsubstituted aryl”) or substituted (a“substituted aryl”) with one or more substituents. In certainembodiments, the aryl group is an unsubstituted C₆₋₁₄ aryl. In certainembodiments, the aryl group is a substituted C₆₋₁₄ aryl.

“Aralkyl” is a subset of “alkyl” and refers to an alkyl groupsubstituted by an aryl group, wherein the point of attachment is on thealkyl moiety.

The term “heteroaryl” refers to a radical of a 5-14 membered monocyclicor polycyclic (e.g., bicyclic, tricyclic) 4n+2 aromatic ring system(e.g., having 6, 10, or 14 π electrons shared in a cyclic array) havingring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ringsystem, wherein each heteroatom is independently selected from nitrogen,oxygen, and sulfur (“5-14 membered heteroaryl”). In heteroaryl groupsthat contain one or more nitrogen atoms, the point of attachment can bea carbon or nitrogen atom, as valency permits. Heteroaryl polycyclicring systems can include one or more heteroatoms in one or both rings.“Heteroaryl” includes ring systems wherein the heteroaryl ring, asdefined above, is fused with one or more carbocyclyl or heterocyclylgroups wherein the point of attachment is on the heteroaryl ring, and insuch instances, the number of ring members continue to designate thenumber of ring members in the heteroaryl ring system. “Heteroaryl” alsoincludes ring systems wherein the heteroaryl ring, as defined above, isfused with one or more aryl groups wherein the point of attachment iseither on the aryl or heteroaryl ring, and in such instances, the numberof ring members designates the number of ring members in the fusedpolycyclic (aryl/heteroaryl) ring system. Polycyclic heteroaryl groupswherein one ring does not contain a heteroatom (e.g., indolyl,quinolinyl, carbazolyl, and the like) the point of attachment can be oneither ring, i.e., either the ring bearing a heteroatom (e.g.,2-indolyl) or the ring that does not contain a heteroatom (e.g.,5-indolyl).

In some embodiments, a heteroaryl group is a 5-10 membered aromatic ringsystem having ring carbon atoms and 1-4 ring heteroatoms provided in thearomatic ring system, wherein each heteroatom is independently selectedfrom nitrogen, oxygen, and sulfur (“5-10 membered heteroaryl”). In someembodiments, a heteroaryl group is a 5-8 membered aromatic ring systemhaving ring carbon atoms and 1-4 ring heteroatoms provided in thearomatic ring system, wherein each heteroatom is independently selectedfrom nitrogen, oxygen, and sulfur (“5-8 membered heteroaryl”). In someembodiments, a heteroaryl group is a 5-6 membered aromatic ring systemhaving ring carbon atoms and 1-4 ring heteroatoms provided in thearomatic ring system, wherein each heteroatom is independently selectedfrom nitrogen, oxygen, and sulfur (“5-6 membered heteroaryl”). In someembodiments, the 5-6 membered heteroaryl has 1-3 ring heteroatomsselected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen,oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Unlessotherwise specified, each instance of a heteroaryl group isindependently unsubstituted (an “unsubstituted heteroaryl”) orsubstituted (a “substituted heteroaryl”) with one or more substituents.In certain embodiments, the heteroaryl group is an unsubstituted 5-14membered heteroaryl. In certain embodiments, the heteroaryl group is asubstituted 5-14 membered heteroaryl.

Exemplary 5-membered heteroaryl groups containing 1 heteroatom include,without limitation, pyrrolyl, furanyl, and thiophenyl. Exemplary5-membered heteroaryl groups containing 2 heteroatoms include, withoutlimitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, andisothiazolyl. Exemplary 5-membered heteroaryl groups containing 3heteroatoms include, without limitation, triazolyl, oxadiazolyl, andthiadiazolyl. Exemplary 5-membered heteroaryl groups containing 4heteroatoms include, without limitation, tetrazolyl. Exemplary6-membered heteroaryl groups containing 1 heteroatom include, withoutlimitation, pyridinyl. Exemplary 6-membered heteroaryl groups containing2 heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, andpyrazinyl. Exemplary 6-membered heteroaryl groups containing 3 or 4heteroatoms include, without limitation, triazinyl and tetrazinyl,respectively. Exemplary 7-membered heteroaryl groups containing 1heteroatom include, without limitation, azepinyl, oxepinyl, andthiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include, withoutlimitation, indolyl, isoindolyl, indazolyl, benzotriazolyl,benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl,benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl,benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, andpurinyl. Exemplary 6,6-bicyclic heteroaryl groups include, withoutlimitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl,cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. Exemplarytricyclic heteroaryl groups include, without limitation,phenanthridinyl, dibenzofuranyl, carbazolyl, acridinyl, phenothiazinyl,phenoxazinyl and phenazinyl.

“Heteroaralkyl” is a subset of “alkyl” and refers to an alkyl groupsubstituted by a heteroaryl group, wherein the point of attachment is onthe alkyl moiety.

The term “unsaturated bond” refers to a double or triple bond.

The term “unsaturated” or “partially unsaturated” refers to a moietythat includes at least one double or triple bond.

The term “saturated” refers to a moiety that does not contain a doubleor triple bond, i.e., the moiety only contains single bonds.

Affixing the suffix “ene” to a group indicates the group is a divalentmoiety, e.g., alkylene is the divalent moiety of alkyl, alkenylene isthe divalent moiety of alkenyl, alkynylene is the divalent moiety ofalkynyl, heteroalkylene is the divalent moiety of heteroalkyl,heteroalkenylene is the divalent moiety of heteroalkenyl,heteroalkynylene is the divalent moiety of heteroalkynyl, carbocyclyleneis the divalent moiety of carbocyclyl, heterocyclylene is the divalentmoiety of heterocyclyl, arylene is the divalent moiety of aryl, andheteroarylene is the divalent moiety of heteroaryl.

A group is optionally substituted unless expressly provided otherwise.In certain embodiments, alkyl, alkenyl, alkynyl, heteroalkyl,heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, andheteroaryl groups are optionally substituted. “Optionally substituted”refers to a group which may be substituted or unsubstituted (e.g.,“substituted” or “unsubstituted” alkyl, “substituted” or “unsubstituted”alkenyl, “substituted” or “unsubstituted” alkynyl, “substituted” or“unsubstituted” heteroalkyl, “substituted” or “unsubstituted”heteroalkenyl, “substituted” or “unsubstituted” heteroalkynyl,“substituted” or “unsubstituted” carbocyclyl, “substituted” or“unsubstituted” heterocyclyl, “substituted” or “unsubstituted” aryl or“substituted” or “unsubstituted” heteroaryl group). In general, the term“substituted” means that at least one hydrogen present on a group isreplaced with a permissible substituent, e.g., a substituent which uponsubstitution results in a stable compound, e.g., a compound which doesnot spontaneously undergo transformation such as by rearrangement,cyclization, elimination, or other reaction. Unless otherwise indicated,a “substituted” group has a substituent at one or more substitutablepositions of the group, and when more than one position in any givenstructure is substituted, the substituent is either the same ordifferent at each position. The term “substituted” is contemplated toinclude substitution with all permissible substituents of organiccompounds, and includes any of the substituents described herein thatresults in the formation of a stable compound. The present disclosurecontemplates any and all such combinations in order to arrive at astable compound. For purposes of this disclosure, heteroatoms such asnitrogen may have hydrogen substituents and/or any suitable substituentas described herein which satisfy the valencies of the heteroatoms andresults in the formation of a stable moiety.

Exemplary carbon atom substituents include, hut are not limited to,halogen, —CN, —NO₂, —N₃, —SO₂H, —SO₃H, —OH, —OR^(aa), —ON(R^(bb))₂,—N(R^(bb))₂, —N(R^(bb))₃ ⁺X⁻, —N(OR^(cc))R^(bb), —SH, —SR^(aa),—SSR^(cc), —C(═O)R^(aa), —CO₂H, —CHO, —C(OR^(cc))₂, —CO₂R^(aa),—OC(═O)R^(aa), —OCO₂R^(aa), —C(═O)N(R^(bb))₂, —OC(═O)N(R^(bb))₂,—NR^(bb)C(═O)R^(aa), —NR^(bb)CO₂R^(aa), —NR^(bb)C(═O)N(R^(bb))₂,—C(═NR^(bb))R^(aa), —C(═NR^(bb))OR^(aa), —OC(═NR^(bb))R^(aa),—OC(═NR^(bb))OR^(aa), —C(═NR^(bb))N(R^(bb))₂, —OC(═NR^(bb))N(R^(bb))₂,—NR^(bb)C(═NR^(bb))N(R^(bb))₂—C(═O)NR^(bb)SO₂R^(aa), —NR^(bb)SO₂R^(aa),—SO₂N(R^(bb))₂, —SO₂R^(aa), —SO₂OR^(aa), —OSO₂R^(aa), —S(═O)R^(aa),—OS(═O)R^(aa), —Si(R^(aa))₃, —OSi(R^(aa))₃—C(═S)N(R^(bb))₂,—C(═O)SR^(aa), —C(═S)SR^(aa), —SC(═S)SR^(aa), —SC(═O)SR^(aa),—OC(═O)SR^(aa), —SC(═O)OR^(aa), —SC(═O)R^(aa), —P(═O)(R^(aa))₂,—P(═O)(OR^(cc))₂, —OP(═O)(R^(aa))₂, —OP(═O)(OR^(cc))₂,—P(═O)(N(R^(bb))₂)₂, —OP(═O)(N(R^(bb))₂)₂, —NR^(bb)P(═O)(R^(aa))₂,—NR^(bb)P(═O)(OR^(cc))₂, —NR^(bb)P(═O)(N(R^(bb))₂)₂, —P(R^(cc))₂,—P(OR^(cc))₂, —P(R^(cc))₃ ⁺X⁻, —P(OR^(cc))₃ ⁺X⁻, —P(R^(cc))₄,—P(OR^(cc))₄, —OP(R^(cc))₂, —OP(R^(cc))₃ ⁺X⁻, —PP(OR^(cc))₂,—OP(OR^(cc))₃ ⁺X⁻, —OP(R^(cc))₄, —OP(OR^(cc))₄, —B(R^(aa))₂,—B(OR^(cc))₂, —BR^(aa)(OR^(cc)), C₁₋₁₀ alkyl, C₁₋₁₀ perhaloalkyl, C₂₋₁₀alkenyl, C₂₋₁₀ alkynyl, heteroC₁₋₁₀ alkyl, heteroC₂₋₁₀ alkenyl,heteroC₂₋₁₀ alkynyl, C₃₋₁₀ carbocyclyl, 3-14 membered heterocyclyl,C₆₋₁₄ aryl, and 5-14 membered heteroaryl, wherein each alkyl, alkenyl,alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl,heterocyclyl, aryl, and heteroaryl is independently substituted with 0,1, 2, 3, 4, or 5 R^(dd) groups; wherein X⁻ is a counterion;

or two geminal hydrogens on a carbon atom are replaced with the group═O, ═S, ═NN(R^(bb))₂, ═NNR^(bb)C(═O)R^(aa), ═NNR^(bb)C(═O)OR^(aa),═NNR^(bb)S(═O)₂R^(aa), ═NR^(bb), or ═NOR^(cc);

each instance of R^(aa) is, independently, selected from C₁₋₁₀ alkyl,C₁₋₁₀ perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, heteroC₁₋₁₀ alkyl,heteroC₂₋₁₀alkenyl, heteroC₂₋₁₀alkynyl, C₃₋₁₀ carbocyclyl, 3-14 memberedheterocyclyl, C₆₋₁₄ aryl, and 5-14 membered heteroaryl, or two R^(aa)groups are joined to form a 3-14 membered heterocyclyl or 5-14 memberedheteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl,heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, andheteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R^(dd)groups;

each instance of R^(bb) is, independently, selected from hydrogen, —OH,—OR^(aa), —N(R^(cc))₂, —CN, —C(═O)R^(aa), —C(═O)N(R^(cc))₂, —CO₂R^(aa),—SO₂R^(aa), —C(═NR^(cc))OR^(aa), —C(═NR^(cc))N(R^(cc))₂, —SO₂N(R^(cc))₂,—SO₂R^(cc), —SO₂OR^(cc), —SOR^(aa), —C(═S)N(R^(cc))₂, —C(═O)SR^(cc),—C(═S)SR^(cc), —P(═O)(R^(aa))₂, —P(═O)(OR^(cc))₂, —P(═O)(N(R^(cc))₂)₂,C₁₋₁₀ alkyl, C₁₋₁₀ perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl,heteroC₁₋₁₀alkyl, heteroC₂₋₁₀alkenyl, heteroC₂₋₁₀alkynyl, C₃₋₁₀carbocyclyl, 3-14 membered heterocyclyl, C₆₋₁₄ aryl, and 5-14 memberedheteroaryl, or two R^(bb) groups are joined to form a 3-14 memberedheterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl,alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl,carbocyclyl, heterocyclyl, aryl, and heteroaryl is independentlysubstituted with 0, 1, 2, 3, 4, or 5 R^(dd) groups; wherein X⁻ is acounterion;

each instance of R^(cc) is, independently, selected from hydrogen, C₁₋₁₀alkyl, C₁₋₁₀ perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, heteroC₁₋₁₀alkyl, heteroC₂₋₁₀ alkenyl, heteroC₂₋₁₀ alkynyl, C₃₋₁₀ carbocyclyl, 3-14membered heterocyclyl, C₆₋₁₄ aryl, and 5-14 membered heteroaryl, or twoR^(cc) groups are joined to form a 3-14 membered heterocyclyl or 5-14membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl,heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl,aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or5 R^(dd) groups;

each instance of R^(dd) is, independently, selected from halogen, —CN,—NO₂, —N₃, —SO₂H, —SO₃H, —OH, —OR^(ee), —ON(R^(ff))₂, —N(R^(ff))₂,—N(R^(ff))₃ ⁺X⁻, —N(OR^(ee))R^(ff), —SH, —SR^(ee), —SSR^(ee),—C(═O)R^(ee), —CO₂R^(ee), —OC(═O)R^(ee), —OCO₂R^(ee), —C(═O)N(R^(ff))₂,—OC(═O)N(R^(ff))₂, —NR^(ff)C(═O)R^(ee), —NR^(ff)CO₂R^(ee),—NR^(ff)C(═O)N(R^(ff))₂, —C(═NR^(ff))OR^(ee), —OC(═NR^(ff))R^(ee),—OC(═NR^(ff))OR^(ee), —C(═NR^(ff))N(R^(ff))₂, —OC(═NR^(ff))N(R^(ff))₂,—NR^(ff)C(═NR^(ff))N(R^(ff))₂, —NR^(ff)SO₂R^(ee), —SO₂N(R^(ff))₂,—SO₂R^(ee), —SO₂OR^(ee), —OSO₂R^(ee), —S(═O)R^(ee), —Si(R^(ee))₃,—OSi(R^(ee))₃, —C(═S)N(R^(ff))₂, —C(═O)SR^(ee), —C(═S)SR^(ee),—SC(═S)SR^(ee), —P(═O)(OR^(ee))₂, —P(═O)(R^(ee))₂, —OP(═O)(R^(ee))₂,—OP(═O)(OR^(ee))₂, C₁₋₆ alkyl, C₁₋₆ perhaloalkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, heteroC₁₋₆alkyl, heteroC₂₋₆alkenyl, heteroC₂₋₆alkynyl, C₃₋₁₀carbocyclyl, 3-10 membered heterocyclyl, C₆₋₁₀ aryl, 5-10 memberedheteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl,heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, andheteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R^(gg)groups, or two geminal R^(dd) substituents can be joined to form ═O or═S; wherein X⁻ is a counterion;

each instance of R^(ee) is, independently, selected from C₁₋₆ alkyl,C₁₋₆ perhaloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, heteroC₁₋₆ alkyl,heteroC₂₋₆alkenyl, heteroC₂₋₆ alkynyl, C₃₋₁₀ carbocyclyl, C₆₋₁₀ aryl,3-10 membered heterocyclyl, and 3-10 membered heteroaryl, wherein eachalkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl,carbocyclyl, heterocyclyl, aryl, and heteroaryl is independentlysubstituted with 0, 1, 2, 3, 4, or 5 R^(gg) groups;

each instance of R^(ff) is, independently, selected from hydrogen, C₁₋₆alkyl, C₁₋₆ perhaloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, heteroC₁₋₆alkyl,heteroC₂₋₆alkenyl, heteroC₂₋₆alkynyl, C₃₋₁₀ carbocyclyl, 3-10 memberedheterocyclyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl, or two R^(ff)groups are joined to form a 3-10 membered heterocyclyl or 5-10 memberedheteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl,heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, andheteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R^(gg)groups; and

each instance of R^(gg) is, independently, halogen, —CN, —NO₂, —N₃,—SO₂H, —SO₃H, —OH, —OC₁₋₆ alkyl, —ON(C₁₋₆ alkyl)₂, —N(C₁₋₆ alkyl)₂,—N(C₁₋₆ alkyl)₃ ⁺X⁻, —NH(C₁₋₆ alkyl)₂ ⁺X⁻, —NH₂(C₁₋₆ alkyl)⁺X⁻, —NH₃⁺X⁻, —N(OC₁₋₆ alkyl)(C₁₋₆ alkyl), —N(OH)(C₁₋₆ alkyl), —NH(OH), —SH,—SC₁₋₆ alkyl, —SS(C₁₋₆ alkyl), —C(═O)(C₁₋₆ alkyl), —CO₂H, —CO₂(C₁₋₆alkyl), —OC(═O)(C₁₋₆ alkyl), —OCO₂(C₁₋₆ alkyl), —C(═O)NH₂, —C(═O)N(C₁₋₆alkyl)₂, —OC(═O)NH(C₁₋₆ alkyl), —NHC(═O)(C₁₋₆ alkyl), —N(C₁₋₆alkyl)C(═O)(C₁₋₆ alkyl), —NHCO₂(C₁₋₆ alkyl), —NHC(═O)N(C₁₋₆ alkyl)₂,—NHC(═O)NH(C₁₋₆ alkyl), —NHC(═O)NH₂, —C(═NH)O(C₁₋₆ alkyl), —OC(═NH)(C₁₋₆alkyl), —OC(═NH)OC₁₋₆ alkyl, —C(═NH)N(C₁₋₆ alkyl)₂, —C(═NH)NH(C₁₋₆alkyl), —C(═NH)NH₂, —OC(═NH)N(C₁₋₆ alkyl)₂, —OC(NH)NH(C₁₋₆ alkyl),—OC(NH)NH₂, —NHC(NH)N(C₁₋₆ alkyl)₂, —NHC(═NH)NH₂, —NHSO₂(C₁₋₆ alkyl),—SO₂N(C₁₋₆ alkyl)₂, —SO₂NH(C₁₋₆ alkyl), —SO₂NH₂, —SO₂C₁₋₆ alkyl,—SO₂OC₁₋₆ alkyl, —OSO₂C₁₋₆ alkyl, —SOC₁₋₆ alkyl, —Si(C₁₋₆ alkyl)₃,—OSi(C₁₋₆ alkyl)₃-C(═S)N(C₁₋₆ alkyl)₂, C(═S)NH(C₁₋₆ alkyl), C(═S)NH₂,—C(═O)S(C₁₋₆ alkyl), —C(═S)SC₁₋₆ alkyl, —SC(═S)SC₁₋₆ alkyl, —P(═O)(OC₁₋₆alkyl)₂, —P(═O)(C₁₋₆ alkyl)₂, —OP(═O)(C₁₋₆ alkyl)₂, —OP(═O)(OC₁₋₆alkyl)₂, C₁₋₆ alkyl, C₁₋₆ perhaloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,heteroC₁₋₆alkyl, heteroC₂₋₆alkenyl, heteroC₂₋₆alkynyl, C₃₋₁₀carbocyclyl, C₆₋₁₀ aryl, 3-10 membered heterocyclyl, 5-10 memberedheteroaryl; or two geminal R^(gg) substituents can be joined to form ═Oor ═S; wherein X⁻ is a counterion.

The term “halo” or “halogen” refers to fluorine (fluoro, —F), chlorine(chloro, —Cl), bromine (bromo, —Br), or iodine (iodo, —I).

The term “hydroxyl” or “hydroxy” refers to the group —OH. The term“substituted hydroxyl” or “substituted hydroxyl,” by extension, refersto a hydroxyl group wherein the oxygen atom directly attached to theparent molecule is substituted with a group other than hydrogen, andincludes groups selected from —OR^(aa), —ON(R^(bb))₂, —OC(═O)SR^(aa),—OC(═O)R^(aa), —OCO₂R^(aa), —OC(═O)N(R^(bb))₂, —OC(═NR^(bb))R^(aa),—OC(═NR^(bb)) OR^(aa), —OC(═NR^(bb))N(R^(bb))₂, —OS(═O)R^(aa),—OSO₂R^(aa), —OSi(R^(aa))₃, —OP(R^(cc))₂, —OP(R^(cc))₃, —OP(═O)₂R^(aa),—OP(═O)(R^(aa))₂, —OP(═O)(OR^(cc))₂, —OP(═O)₂N(R^(bb))₂, and—OP(═O)(NR^(bb))₂, wherein R^(aa), R^(bb), and R^(cc) are as definedherein.

The term “thiol” or “thio” refers to the group —SH. The term“substituted thiol” or “substituted thio,” by extension, refers to athiol group wherein the sulfur atom directly attached to the parentmolecule is substituted with a group other than hydrogen, and includesgroups selected from —SR^(aa), —S═SR^(cc), —SC(═O)SR^(aa),—SC(═O)SR^(aa), —SC(═O)OR^(aa), and —SC(═O)R^(aa), wherein R^(aa) andR^(cc) are as defined herein.

The term “amino” refers to the group —NH₂. The term “substituted amino,”by extension, refers to a monosubstituted amino, a disubstituted amino,or a trisubstituted amino. In certain embodiments, the “substitutedamino” is a monosubstituted amino or a disubstituted amino group.

The term “monosubstituted amino” refers to an amino group wherein thenitrogen atom directly attached to the parent molecule is substitutedwith one hydrogen and one group other than hydrogen, and includes groupsselected from —NH(R^(bb)), —NHC(═O)R^(aa), —NHCO₂R^(aa),—NHC(═O)N(R^(bb))₂, —NHC(═NR^(bb))N(R^(bb))₂, —NHSO₂R^(aa),—NHP(═O)(OR^(cc))₂, and —NHP(═O)(N(R^(bb))₂)₂, wherein R^(aa), R^(bb)and R^(cc) are as defined herein, and wherein R^(bb) of the group—NH(R^(bb)) is not hydrogen.

The term “disubstituted amino” refers to an amino group wherein thenitrogen atom directly attached to the parent molecule is substitutedwith two groups other than hydrogen, and includes groups selected from—N(R^(bb))₂, —NR^(bb)C(═O)R^(aa), —NR^(bb)CO₂R^(aa),—NR^(bb)C(═O)N(R^(bb))₂, —NR^(bb)C(═NR^(bb))N(R^(bb))₂,—NR^(bb)SO₂R^(aa), —NR^(bb)P(═O)(OR^(cc))₂, and—NR^(bb)P(═O)(N(R^(bb))₂)₂, wherein R^(aa), R^(bb), and R^(cc) are asdefined herein, with the proviso that the nitrogen atom directlyattached to the parent molecule is not substituted with hydrogen.

The term “trisubstituted amino” refers to an amino group wherein thenitrogen atom directly attached to the parent molecule is substitutedwith three groups, and includes groups selected from —N(R^(bb))₃ and—N(R^(bb))₃ ⁺X⁻, wherein R^(bb) and X⁻ are as defined herein.

The term “sulfonyl” refers to a group selected from —SO₂N(R^(bb))₂,—SO₂R^(aa), and —SO₂OR^(aa), wherein R^(aa) and R^(bb) are as definedherein.

The term “sulfinyl” refers to the group —S(═O)R^(aa), wherein R^(aa) isas defined herein.

The term “carbonyl” refers a group wherein the carbon directly attachedto the parent molecule is sp² hybridized, and is substituted with anoxygen, nitrogen or sulfur atom, e.g., a group selected from ketones(—C(═O)R^(aa)), carboxylic acids (—CO₂H), aldehydes (—CHO), esters(—CO₂R^(aa), —C(═O)SR^(aa), —C(═S)SR^(aa)), amides (—C(═O)N(R^(bb))₂,—C(═O)NR^(bb)SO₂R^(aa), —C(═S)N(R^(bb))₂), and imines(—C(═NR^(bb))R^(aa), —C(═NR^(bb))OR^(aa)), —C(═NR^(bb))N(R^(bb))₂),wherein R^(aa) and R^(bb) are as defined herein.

The term “silyl” refers to the group —Si(R^(aa))₃, wherein R^(aa) is asdefined herein.

The term “oxo” refers to the group ═O, and the term “thiooxo” refers tothe group ═S.

Nitrogen atoms can be substituted or unsubstituted as valency permits,and include primary, secondary, tertiary, and quaternary nitrogen atoms.Exemplary nitrogen atom substituents include, but are not limited to,hydrogen, —OH, —OR^(aa), —N(R^(cc))₂, —CN, —C(═O)R^(aa),—C(═O)N(R^(cc))₂, —CO₂R^(aa), —SO₂R^(aa), —C(═NR^(bb))R^(aa),—C(═NR^(cc))OR^(aa), —C(═NR^(cc))N(R^(cc))₂, —SO₂N(R^(cc))₂, —SO₂R^(cc),—SO₂OR^(cc), —SOR^(aa), —C(═S)N(R^(cc))₂, —C(═O)SR^(cc), —C(═S)SR^(cc),—P(═O)(OR^(cc))₂, —P(═O)(R^(aa))₂, —P(═O)(N(R^(cc))₂)₂, C₁₋₁₀ alkyl,C₁₋₁₀ perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, heteroC₁₋₁₀alkyl,heteroC₂₋₁₀alkenyl, heteroC₂₋₁₀alkynyl, C₃₋₁₀ carbocyclyl, 3-14 memberedheterocyclyl, C₆₋₁₄ aryl, and 5-14 membered heteroaryl, or two R^(cc)groups attached to an N atom are joined to form a 3-14 memberedheterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl,alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl,carbocyclyl, heterocyclyl, aryl, and heteroaryl is independentlysubstituted with 0, 1, 2, 3, 4, or 5 R^(dd) groups, and wherein R^(aa),R^(bb), R^(cc) and R^(dd) are as defined above.

In certain embodiments, the substituent present on the nitrogen atom isan nitrogen protecting group (also referred to herein as an “aminoprotecting group”). Nitrogen protecting groups include, but are notlimited to, —OH, —OR^(aa), —N(R^(cc))₂, —C(═O)R^(aa), —C(═O)N(R^(cc))₂,—CO₂R^(aa), —SO₂R^(aa), —C(═NR^(cc))R^(aa), —C(═NR^(cc))OR^(aa),—C(═NR^(cc))N(R^(cc))₂, —SO₂N(R^(cc))₂, —SO₂R^(cc), —SO₂OR^(cc),—SOR^(aa), —C(═S)N(R^(cc))₂, —C(═O)SR^(cc), —C(═S)SR^(cc), C₁₋₁₀ alkyl(e.g., aralkyl, heteroaralkyl), C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl,heteroC₁₋₁₀ alkyl, heteroC₂₋₁₀ alkenyl, heteroC₂₋₁₀ alkynyl, C₃₋₁₀carbocyclyl, 3-14 membered heterocyclyl, C₆₋₁₄ aryl, and 5-14 memberedheteroaryl groups, wherein each alkyl, alkenyl, alkynyl, heteroalkyl,heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aralkyl, aryl,and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5R^(dd) groups, and wherein R^(aa), R^(bb), R^(cc) and R^(dd) are asdefined herein. Nitrogen protecting groups are well known in the art andinclude those described in detail in Protecting Groups in OrganicSynthesis, T. W. Greene and P. G. M. Wuts, 3^(rd) edition, John Wiley &Sons, 1999, incorporated herein by reference.

For example, nitrogen protecting groups such as amide groups (e.g.,—C(═O)R^(aa)) include, but are not limited to, formamide, acetamide,chloroacetamide, trichloroacetamide, trifluoroacetamide,phenylacetamide, 3-phenylpropanamide, picolinamide,3-pyridylcarboxamide, N-benzoylphenylalanyl derivative, benzamide,p-phenylbenzamide, o-nitophenylacetamide, o-nitrophenoxyacetamide,acetoacetamide, (N′-dithiobenzyloxyacylamino)acetamide,3-(phydroxyphenyl)propanamide, 3-(o-nitrophenyl)propanamide,2-methyl-2-(o-nitrophenoxy)propanamide,2-methyl-2-(o-phenylazophenoxy)propanamide, 4-chlorobutanamide,3-methyl-3-nitrobutanamide, o-nitrocinnamide, N-acetylmethioninederivative, o-nitrobenzamide and o-(benzoyloxymethyl)benzamide.

Nitrogen protecting groups such as carbamate groups (e.g.,—C(═O)OR^(aa)) include, but are not limited to, methyl carbamate, ethylcarbamate, 9-fluorenylmethyl carbamate (Fmoc),9-(2-sulfo)fluorenylmethyl carbamate, 9-(2,7-dibromo)fluorenylmethylcarbamate,2,7-di-t-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)]methylcarbamate (DBD-Tmoc), 4-methoxyphenacyl carbamate (Phenoc),2,2,2-trichloroethyl carbamate (Troc), 2-trimethylsilylethyl carbamate(Teoc), 2-phenylethyl carbamate (hZ), 1-(1-adamantyl)-1-methylethylcarbamate (Adpoc), 1,1-dimethyl-2-haloethyl carbamate,1,1-dimethyl-2,2-dibromoethyl carbamate (DB-t-BOC),1,1-dimethyl-2,2,2-trichloroethyl carbamate (TCBOC),1-methyl-1-(4-biphenylyl)ethyl carbamate (Bpoc),1-(3,5-di-t-butylphenyl)-1-methylethyl carbamate (t-Bumeoc), 2-(2′- and4′-pyridyl)ethyl carbamate (Pyoc), 2-(N,N-dicyclohexylcarboxamido)ethylcarbamate, t-butyl carbamate (BOC or Boc), 1-adamantyl carbamate (Adoc),vinyl carbamate (Voc), allyl carbamate (Alloc), 1-isopropylallylcarbamate (Ipaoc), cinnamyl carbamate (Coc), 4-nitrocinnamyl carbamate(Noc), 8-quinolyl carbamate, N-hydroxypiperidinyl carbamate, alkyldithiocarbamate, benzyl carbamate (Cbz), p-methoxybenzyl carbamate (Moz),p-nitrobenzyl carbamate, p-bromobenzyl carbamate, p-chlorobenzylcarbamate, 2,4-dichlorobenzyl carbamate, 4-methylsulfinylbenzylcarbamate (Msz), 9-anthrylmethyl carbamate, diphenylmethyl carbamate,2-methylthioethyl carbamate, 2-methylsulfonylethyl carbamate,2-(p-toluenesulfonyl)ethyl carbamate, [2-(1,3-dithianyl)]methylcarbamate (Dmoc), 4-methylthiophenyl carbamate (Mtpc),2,4-dimethylthiophenyl carbamate (Bmpc), 2-phosphonioethyl carbamate(Peoc), 2-triphenylphosphonioisopropyl carbamate (Ppoc),1,1-dimethyl-2-cyanoethyl carbamate, m-chloro-p-acyloxybenzyl carbamate,p-(dihydroxyboryl)benzyl carbamate, 5-benzisoxazolylmethyl carbamate,2-(trifluoromethyl)-6-chromonylmethyl carbamate (Tcroc), m-nitrophenylcarbamate, 3,5-dimethoxybenzyl carbamate, o-nitrobenzyl carbamate,3,4-dimethoxy-6-nitrobenzyl carbamate, phenyl(o-nitrophenyl)methylcarbamate, t-amyl carbamate, S-benzyl thiocarbamate, p-cyanobenzylcarbamate, cyclobutyl carbamate, cyclohexyl carbamate, cyclopentylcarbamate, cyclopropylmethyl carbamate, p-decyloxybenzyl carbamate,2,2-dimethoxyacylvinyl carbamate, o-(N,N-dimethylcarboxamido)benzylcarbamate, 1,1-dimethyl-3-(N,N-dimethylcarboxamido)propyl carbamate,1,1-dimethylpropynyl carbamate, di(2-pyridyl)methyl carbamate,2-furanylmethyl carbamate, 2-iodoethyl carbamate, isobornyl carbamate,isobutyl carbamate, isonicotinyl carbamate,p-(p′-methoxyphenylazo)benzyl carbamate, 1-methylcyclobutyl carbamate,1-methylcyclohexyl carbamate, 1-methyl-1-cyclopropylmethyl carbamate,1-methyl-1-(3,5-dimethoxyphenyl)ethyl carbamate,1-methyl-1-(p-phenylazophenyl)ethyl carbamate, 1-methyl-1-phenylethylcarbamate, 1-methyl-1-(4-pyridyl)ethyl carbamate, phenyl carbamate,p-(phenylazo)benzyl carbamate, 2,4,6-tri-t-butylphenyl carbamate,4-(trimethylammonium)benzyl carbamate, and 2,4,6-trimethylbenzylcarbamate.

Nitrogen protecting groups such as sulfonamide groups (e.g.,—S(═O)₂R^(aa)) include, but are not limited to, p-toluenesulfonamide(Ts), benzenesulfonamide, 2,3,6-trimethyl-4-methoxybenzenesulfonamide(Mtr), 2,4,6-trimethoxybenzenesulfonamide (Mtb),2,6-dimethyl-4-methoxybenzenesulfonamide (Pme),2,3,5,6-tetramethyl-4-methoxybenzenesulfonamide (Mte),4-methoxybenzenesulfonamide (Mbs), 2,4,6-trimethylbenzenesulfonamide(Mts), 2,6-dimethoxy-4-methylbenzenesulfonamide (iMds),2,2,5,7,8-pentamethylchroman-6-sulfonamide (Pmc), methanesulfonamide(Ms), β-trimethylsilylethanesulfonamide (SES), 9-anthracenesulfonamide,4-(4′,8′-dimethoxynaphthylmethyl)benzenesulfonamide (DNMBS),benzylsulfonamide, trifluoromethylsulfonamide, and phenacylsulfonamide.

Other nitrogen protecting groups include, but are not limited to,phenothiazinyl-(10)-acyl derivative, N′-p-toluenesulfonylaminoacylderivative, N′-phenylaminothioacyl derivative, N-benzoylphenylalanylderivative, N-acetylmethionine derivative,4,5-diphenyl-3-oxazolin-2-one, N-phthalimide, N-dithiasuccinimide (Dts),N-2,3-diphenylmaleimide, N-2,5-dimethylpyrrole,N-1,1,4,4-tetramethyldisilylazacyclopentane adduct (STABASE),5-substituted 1,3-dimethyl-1,3,5-triazacyclohexan-2-one, 5-substituted1,3-dibenzyl-1,3,5-triazacyclohexan-2-one, 1-substituted3,5-dinitro-4-pyridone, N-methylamine, N-allylamine,N-[2-(trimethylsilyl)ethoxy]methylamine (SEM), N-3-acetoxypropylamine,N-(1-isopropyl-4-nitro-2-oxo-3-pyroolin-3-yl)amine, quaternary ammoniumsalts, N-benzylamine, N-di(4-methoxyphenyl)methylamine,N-5-dibenzosuberylamine, N-triphenylmethylamine (Tr),N-[(4-methoxyphenyl)diphenylmethyl]amine (MMTr),N-9-phenylfluorenylamine (PhF),N-2,7-dichloro-9-fluorenylmethyleneamine, N-ferrocenylmethylamino (Fcm),N-2-picolylamino N′-oxide, N-1,1-dimethylthiomethyleneamine,N-benzylideneamine, N-p-methoxybenzylideneamine,N-diphenylmethyleneamine, N-[(2-pyridyl)mesityl]methyleneamine,N—(N′,N′-dimethylaminomethylene)amine, N,N′-isopropylidenediamine,N-p-nitrobenzylideneamine, N-salicylideneamine,N-5-chlorosalicylideneamine,N-(5-chloro-2-hydroxyphenyl)phenylmethyleneamine,N-cyclohexylideneamine, N-(5,5-dimethyl-3-oxo-1-cyclohexenyl)amine,N-borane derivative, N-diphenylborinic acid derivative,N-[phenyl(pentaacylchromium- or tungsten)acyl]amine, N-copper chelate,N-zinc chelate, N-nitroamine, N-nitrosoamine, amine N-oxide,diphenylphosphinamide (Dpp), dimethylthiophosphinamide (Mpt),diphenylthiophosphinamide (Ppt), dialkyl phosphoramidates, dibenzylphosphoramidate, diphenyl phosphoramidate, benzenesulfenamide,o-nitrobenzenesulfenamide (Nps), 2,4-dinitrobenzenesulfenamide,pentachlorobenzenesulfenamide, 2-nitro-4-methoxybenzenesulfenamide,triphenylmethylsulfenamide, and 3-nitropyridinesulfenamide (Npys).

In certain embodiments, the substituent present on an oxygen atom is anoxygen protecting group (also referred to herein as an “hydroxylprotecting group”). Oxygen protecting groups include, but are notlimited to, —R^(aa), —N(R^(bb))₂, —C(═O)SR^(aa), —C(═O)R^(aa),—CO₂R^(aa), —C(═O)N(R^(bb))₂, —C(═NR^(bb))R^(aa), —C(═NR^(bb))OR^(aa),—C(—NR^(bb))N(R^(bb))₂, —S(═O)R^(aa), —SO₂R^(aa), —Si(R^(aa))₂,—P(R^(cc))₂, —P(R^(cc))₃ ⁺X⁻, —P(OR^(cc))₂, —P(OR^(cc))₃ ⁺X⁻,—P(═O)(R^(aa))₂, —P(═O)(OR^(cc))₂, and —P(═O)(N(R^(bb))) wherein X⁻,R^(aa), R^(bb), and R^(cc) are as defined herein. Oxygen protectinggroups are well known in the art and include those described in detailin Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M.Wuts, 3^(rd) edition, John Wiley & Sons, 1999, incorporated herein byreference.

Exemplary oxygen protecting groups include, but are not limited to,methyl, methoxylmethyl (MOM), methylthiomethyl (MTM), t-butylthiomethyl,(phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM),p-methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM),guaiacolmethyl (GUM), t-butoxymethyl, 4-pentenyloxymethyl (POM),siloxymethyl, 2-methoxyethoxymethyl (MEM), 2,2,2-trichloroethoxymethyl,bis(2-chloroethoxy)methyl, 2-(trimethylsilyl)ethoxymethyl (SEMOR),tetrahydropyranyl (THP), 3-bromotetrahydropyranyl,tetrahydrothiopyranyl, 1-methoxycyclohexyl, 4-methoxytetrahydropyranyl(MTHP), 4-methoxytetrahydrothiopyranyl, 4-methoxytetrahydrothiopyranylS,S-dioxide, 1-[(2-chloro-4-methyl)phenyl]-4-methoxypiperidin-4-yl(CTMP), 1,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl,2,3,3a,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl,1-ethoxyethyl, 1-(2-chloroethoxy)ethyl, 1-methyl-1-methoxyethyl,1-methyl-1-benzyloxyethyl, 1-methyl-1-benzyloxy-2-fluoroethyl,2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-(phenylselenyl)ethyl,t-butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl,benzyl (Bn), p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl,p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl,p-phenylbenzyl, 2-picolyl, 4-picolyl, 3-methyl-2-picolyl N-oxido,diphenylmethyl, p,p′-dinitrobenzhydryl, 5-dibenzosuberyl,triphenylmethyl, α-naphthyldiphenylmethyl,p-methoxyphenyldiphenylmethyl, di(p-methoxyphenyl)phenylmethyl,trip-methoxyphenyl)methyl, 4-(4′-bromophenacyloxyphenyl)diphenylmethyl,4,4′,4″-tris(4,5-dichlorophthalimidophenyl)methyl,4,4′,4″-tris(levulinoyloxyphenyl)methyl,4,4′,4″-tris(benzoyloxyphenyl)methyl,3-(imidazol-1-yl)bis(4′,4″-dimethoxyphenyl)methyl,1,1-bis(4-methoxyphenyl)-1′-pyrenylmethyl, 9-anthryl,9-(9-phenyl)xanthenyl, 9-(9-phenyl-10-oxo)anthryl,1,3-benzodithiolan-2-yl, benzisothiazolyl S,S-dioxido, trimethylsilyl(TMS), triethylsilyl (TES), triisopropylsilyl (TIPS),dimethylisopropylsilyl (IPDMS), diethylisopropylsilyl (DEIPS),dimethylthexylsilyl, t-butyldimethylsilyl (TBDMS), t-butyldiphenylsilyl(TBDPS), tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl,diphenylmethylsilyl (DPMS), t-butylmethoxyphenylsilyl (TBMPS), formate,benzoylformate, acetate, chloroacetate, dichloroacetate,trichloroacetate, trifluoroacetate, methoxyacetate,triphenylmethoxyacetate, phenoxyacetate, p-chlorophenoxyacetate,3-phenylpropionate, 4-oxopentanoate (levulinate),4,4-(ethylenedithio)pentanoate (levulinoyldithioacetal), pivaloate,adamantoate, crotonate, 4-methoxycrotonate, benzoate, p-phenylbenzoate,2,4,6-trimethylbenzoate (mesitoate), methyl carbonate, 9-fluorenylmethylcarbonate (Fmoc), ethyl carbonate, 2,2,2-trichloroethyl carbonate(Troc), 2-(trimethylsilyl)ethyl carbonate (TMSEC), 2-(phenylsulfonyl)ethyl carbonate (Psec), 2-(triphenylphosphonio) ethyl carbonate (Peoc),isobutyl carbonate, vinyl carbonate, allyl carbonate, t-butyl carbonate(BOC or Boc), p-nitrophenyl carbonate, benzyl carbonate, p-methoxybenzylcarbonate, 3,4-dimethoxybenzyl carbonate, o-nitrobenzyl carbonate,p-nitrobenzyl carbonate, S-benzyl thiocarbonate, 4-ethoxy-1-naphthylcarbonate, methyl dithiocarbonate, 2-iodobenzoate, 4-azidobutyrate,4-nitro-4-methylpentanoate, o-(dibromomethyl)benzoate,2-formylbenzenesulfonate, 2-(methylthiomethoxy)ethyl,4-(methylthiomethoxy)butyrate, 2-(methylthiomethoxymethyl)benzoate,2,6-dichloro-4-methylphenoxyacetate,2,6-dichloro-4-(1,1,3,3-tetramethylbutyl)phenoxyacetate,2,4-bis(1,1-dimethylpropyl)phenoxyacetate, chlorodiphenylacetate,isobutyrate, monosuccinate, (E)-2-methyl-2-butenoate,o-(methoxyacyl)benzoate, α-naphthoate, nitrate, alkylN,N,N′,N′-tetramethylphosphorodiamidate, alkyl N-phenylcarbamate,borate, dimethylphosphinothioyl, alkyl 2,4-dinitrophenylsulfenate,sulfate, methanesulfonate (mesylate), benzylsulfonate, and tosylate(Ts).

In certain embodiments, the substituent present on a sulfur atom is asulfur protecting group (also referred to as a “thiol protectinggroup”). Sulfur protecting groups include, but are not limited to,—R^(aa), —N(R^(bb))₂, —C(═O)SR^(aa), —C(═O)R^(aa), —CO₂R^(aa),—C(═O)N(R^(bb))₂, —C(═NR^(bb))R^(aa), —C(═NR^(bb))OR^(aa),—C(═NR^(bb))N(R^(bb))₂, —S(═O)R^(aa), —SO₂R^(aa), —Si(R^(aa))₃,—P(R^(cc))₂, —P(R^(cc))₃ ⁺X⁻, —P(OR^(cc))₂, —P(OR^(cc))₃ ⁺X⁻,—P(═O)(R^(aa))₂, —P(═O)(OR^(cc))₂, and —P(═O)(N(R^(bb))₂)₂, whereinR^(aa), R^(bb), and R^(cc) are as defined herein. Sulfur protectinggroups are well known in the art and include those described in detailin Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M.Wuts, 3^(rd) edition, John Wiley & Sons, 1999, incorporated herein byreference.

A “hydrocarbon chain” refers to a substituted or unsubstituted divalentalkyl, alkenyl, or alkynyl group. A hydrocarbon chain includes (1) oneor more chains of carbon atoms immediately between the two radicals ofthe hydrocarbon chain; (2) optionally one or more hydrogen atoms on thechain(s) of carbon atoms; and (3) optionally one or more substituents(“non-chain substituents,” which are not hydrogen) on the chain(s) ofcarbon atoms. A chain of carbon atoms consists of consecutivelyconnected carbon atoms (“chain atoms”) and does not include hydrogenatoms or heteroatoms. However, a non-chain substituent of a hydrocarbonchain may include any atoms, including hydrogen atoms, carbon atoms, andheteroatoms. For example, hydrocarbon chain —C^(A)H(C^(B)H₂C^(C)H₃)—includes one chain atom C^(A), one hydrogen atom on C^(A), and non-chainsubstituent —(C^(B)H₂C^(C)H₃). The term “C_(x) hydrocarbon chain,”wherein x is a positive integer, refers to a hydrocarbon chain thatincludes x number of chain atom(s) between the two radicals of thehydrocarbon chain. If there is more than one possible value of x, thesmallest possible value of x is used for the definition of thehydrocarbon chain. For example, —CH(C₂H₅)— is a C₁ hydrocarbon chain,and

is a C₃ hydrocarbon chain. When a range of values is used, the meaningof the range is as described herein. For example, a C₃₋₁₀ hydrocarbonchain refers to a hydrocarbon chain where the number of chain atoms ofthe shortest chain of carbon atoms immediately between the two radicalsof the hydrocarbon chain is 3, 4, 5, 6, 7, 8, 9, or 10. A hydrocarbonchain may be saturated (e.g., —(CH₂)₄—). A hydrocarbon chain may also beunsaturated and include one or more C═C and/or C≡C bonds anywhere in thehydrocarbon chain. For instance, —CH═CH—(CH₂)₂—, —CH₂—C≡C—CH₂—, and—C≡C—CH═CH— are all examples of a unsubstituted and unsaturatedhydrocarbon chain. In certain embodiments, the hydrocarbon chain isunsubstituted (e.g., —C≡C— or —(CH₂)₄—). In certain embodiments, thehydrocarbon chain is substituted (e.g., —CH(C₂H₅)— and —CF₂—). Any twosubstituents on the hydrocarbon chain may be joined to form anoptionally substituted carbocyclyl, optionally substituted heterocyclyl,optionally substituted aryl, or optionally substituted heteroaryl ring.For instance,

are all examples of a hydrocarbon chain. In contrast, in certainembodiments,

are not within the scope of the hydrocarbon chains described herein.When a chain atom of a C_(x) hydrocarbon chain is replaced with aheteroatom, the resulting group is referred to as a C_(x) hydrocarbonchain wherein a chain atom is replaced with a heteroatom, as opposed toa C_(x-1) hydrocarbon chain. For example,

is a C₃ hydrocarbon chain wherein one chain atom is replaced with anoxygen atom.

The term “acyl” refers a group wherein the carbon directly attached tothe parent molecule is sp² hybridized, and is substituted with anoxygen, nitrogen, or sulfur atom, e.g., a group selected from ketones(—C(═O)R^(aa)), carboxylic acids (—CO₂H), aldehydes (—CHO), esters(—CO₂R^(aa), —C(═O)SR^(aa), —C(═S)SR^(aa)), amides (—C(═O)N(R^(bb))₂,—C(═O)NR^(bb)SO₂R^(aa), —C(═S)N(R^(bb))²), and imines(—C(═NR^(bb))R^(aa), —C(NR^(bb))OR^(aa)), —C(═NR^(bb))N(R^(bb))₂),wherein R^(aa) and R^(bb) are as defined herein.

The term “Lewis acid” refers to a species as defined by IUPAC, that is“a molecular entity (and the corresponding chemical species) that is anelectron-pair acceptor and therefore able to react with a Lewis base toform a Lewis adduct, by sharing the electron pair furnished by the Lewisbase.” Exemplary Lewis acids include, without limitation, borontrifluoride, aluminum trichloride, tin tetrachloride, titaniumtetrachloride, and iron tribromide.

The term “Brønsted acid” refers to a protic or proton-donating species.Exemplary Brønsted acids include, without limitation, acetic acid,triflic acid, hydrochloric acid, and barbituric acid.

The term “salt” refers to those salts which are derived from suitableinorganic and organic acids and bases. Examples of acid addition saltsare salts of an amino group formed with inorganic acids such ashydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, andperchloric acid or with organic acids such as acetic acid, oxalic acid,maleic acid, tartaric acid, citric acid, succinic acid, or malonic acidor by using other methods known in the art such as ion exchange. Otherexemplary salts include adipate, alginate, ascorbate, aspartate,benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate,camphorsulfonate, citrate, cyclopentanepropionate, digluconate,dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate,glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate,hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate,lauryl sulfate, malate, maleate, malonate, methanesulfonate,2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate,pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate,pivalate, propionate, stearate, succinate, sulfate, tartrate,thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and thelike. Salts derived from appropriate bases include alkali metal,alkaline earth metal, ammonium and N⁺(C₁₋₄ alkyl)₄ ⁻ salts.Representative alkali or alkaline earth metal salts include sodium,lithium, potassium, calcium, magnesium, and the like. Furtherpharmaceutically acceptable salts include, when appropriate, nontoxicammonium, quaternary ammonium, and amine cations formed usingcounterions such as halide, hydroxide, carboxylate, sulfate, phosphate,nitrate, lower alkyl sulfonate, and aryl sulfonate.

The term “solvate” refers to forms of the compound that are associatedwith a solvent, usually by a solvolysis reaction. This physicalassociation may include hydrogen bonding. Conventional solvents includewater, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, and thelike. The compounds described herein may be prepared, e.g., incrystalline form, and may be solvated. Suitable solvates includepharmaceutically acceptable solvates and further include bothstoichiometric solvates and non-stoichiometric solvates. In certaininstances, the solvate will be capable of isolation, for example, whenone or more solvent molecules are incorporated in the crystal lattice ofa crystalline solid. “Solvate” encompasses both solution-phase andisolatable solvates. Representative solvates include hydrates,ethanolates, and methanolates.

The term “hydrate” refers to a compound that is associated with water.Typically, the number of the water molecules contained in a hydrate of acompound is in a definite ratio to the number of the compound moleculesin the hydrate. Therefore, a hydrate of a compound may be represented,for example, by the general formula R.x H₂O, wherein R is the compound,and x is a number greater than 0. A given compound may form more thanone type of hydrate, including, e.g., monohydrates (x is 1), lowerhydrates (x is a number greater than 0 and smaller than 1, e.g.,hemihydrates (R.0.5 H₂O)), and polyhydrates (x is a number greater than1, e.g., dihydrates (R.2 H₂O) and hexahydrates (R.6 H₂O)).

The term “tautomers” or “tautomeric” refers to two or moreinterconvertable compounds resulting from at least one formal migrationof a hydrogen atom and at least one change in valency (e.g., a singlebond to a double bond, a triple bond to a single bond, or vice versa).The exact ratio of the tautomers depends on several factors, includingtemperature, solvent, and pH. Tautomerizations (i.e., the reactionproviding a tautomeric pair) may catalyzed by acid or base. Exemplarytautomerizations include keto-to-enol, amide-to-imide, lactam-to-lactim,enamine-to-imine, and enamine-to-(a different enamine) tautomerizations.

It is also to be understood that compounds that have the same molecularformula but differ in the nature or sequence of bonding of their atomsor the arrangement of their atoms in space are termed “isomers”. Isomersthat differ in the arrangement of their atoms in space are termed“stereoisomers”.

Stereoisomers that are not mirror images of one another are termed“diastereomers” and those that are non-superimposable mirror images ofeach other are termed “enantiomers”. When a compound has an asymmetriccenter, for example, it is bonded to four different groups, a pair ofenantiomers is possible. An enantiomer can be characterized by theabsolute configuration of its asymmetric center and is described by theR- and S-sequencing rules of Cahn and Prelog, or by the manner in whichthe molecule rotates the plane of polarized light and designated asdextrorotatory or levorotatory (i.e., as (+) or (−)-isomersrespectively). A chiral compound can exist as either individualenantiomer or as a mixture thereof. A mixture containing equalproportions of the enantiomers is called a “racemic mixture”.

A “counterion” or “anionic counterion” is a negatively charged groupassociated with a positively charged group in order to maintainelectronic neutrality. An anionic counterion may be monovalent (i.e.,including one formal negative charge). An anionic counterion may also bemultivalent (i.e., including more than one formal negative charge), suchas divalent or trivalent. Exemplary counterions include halide ions(e.g., F⁻, Cl⁻, Br⁻, I⁻), NO₃ ⁻, ClO₄ ⁻, OH⁻, H₂PO₄ ⁻, HCO₃ ⁻, HSO₄ ⁻,sulfonate ions (e.g., methanesulfonate, trifluoromethanesulfonate,p-toluenesulfonate, benzenesulfonate, 10-camphor sulfonate,naphthalene-2-sulfonate, naphthalene-1-sulfonic acid-5-sulfonate,ethan-1-sulfonic acid-2-sulfonate, and the like), carboxylate ions(e.g., acetate, propanoate, benzoate, glycerate, lactate, tartrate,glycolate, gluconate, and the like), BF₄ ⁻, PF₄ ⁻, PF₆ ⁻, AsF₆ ⁻, SbF₆⁻, B[3,5-(CF₃)₂C₆H₃]₄]⁻, B(C₆F₅)₄ ⁻, BPh₄ ⁻, Al(OC(CF₃)₃)₄ ⁻, andcarborane anions (e.g., CB₁₁H₁₂ ⁻ or (HCB₁₁Me₅Br₆)⁻). Exemplarycounterions which may be multivalent include CO₃ ²⁻, HPO₄ ²⁻, PO₄ ³⁻,B₄O₇ ²⁻, SO₄ ²⁻, S₂O₃ ²⁻, carboxylate anions (e.g., tartrate, citrate,fumarate, maleate, malate, malonate, gluconate, succinate, glutarate,adipate, pimelate, suberate, azelate, sebacate, salicylate, phthalates,aspartate, glutamate, and the like), and carboranes.

As used herein, a “leaving group” (LG) is an art-understood termreferring to a molecular fragment that departs with a pair of electronsin heterolytic bond cleavage, wherein the molecular fragment is an anionor neutral molecule. As used herein, a leaving group can be an atom or agroup capable of being displaced by a nucleophile. See, for example,Smith, March Advanced Organic Chemistry 6th ed. (501-502). Exemplaryleaving groups include, but are not limited to, halo (e.g., chloro,bromo, iodo) and activated substituted hydroxyl groups (e.g.,—OC(═O)SR^(aa), —OC(═O)R^(aa), —OCO₂R^(aa), —OC(═O)N(R^(bb))₂,—OC(═NR^(bb))R^(aa), —OC(═NR^(bb))OR^(aa), —OC(═NR^(bb))N(R^(bb))₂,—OS(═O)R^(aa), —OSO₂R^(aa), —OP(R^(cc))₂, —OP(R^(cc))₃, —OP(═O)₂R^(aa),—OP(═O)(R^(aa))₂—, —OP(═O)(OR^(cc))₂, —OP(═O)₂N(R^(bb))₂, and—OP(═O)(NR^(bb))₂, wherein R^(aa), R^(bb), and R^(cc) are as definedherein).

As used herein, use of the phrase “at least one instance” refers to 1,2, 3, 4, or more instances, but also encompasses a range, e.g., forexample, from 1 to 4, from 1 to 3, from 1 to 2, from 2 to 4, from 2 to3, or from 3 to 4 instances, inclusive.

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS OF THE INVENTION

Cr-mediated couplings of organic halides/triflates with aldehydes arevaluable tools to generate compounds with multi-functional groups.Cr-mediated couplings are used in synthesis of complicated macrolidessuch as halichondrin A and B. Depending on the mode of activation,Cr-mediated couplings are divided into three sub-groups: (1)Ni/Cr-mediated alkenylation, alkynylation, and arylation, (2) Co orFe/Cr-mediated alkylation, 2-haloallyl-ation and (propargylation), and(3) Cr-mediated allylation and propargylation (see, e.g., Saccomano, N.A. in Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.;Pergamon: Oxford, 1991; Vol. 1, p 173).

This Cr-mediated coupling process is a Grignard-type carbonyl additionreaction. It displays selectivity towards aldehydes over other carbonylcompounds. Activation of halides or triflates in the presence ofaldehydes provides not only an experimental convenience, but also anopportunity to achieve chemical transformations in an unconventionalmanner, e.g., cyclization. The most valuable feature of this coupling isits compatibility with a wide range of functional groups. This uniquepotential is especially important when applied to polyfunctionalmolecules, especially in the late-stages of a multi-step synthesis.Provided herein are chromium-mediated coupling reactions which areapplicable to the preparation of halichondrins (e.g., halichondrin A, B,C; norhalichondrin A, B, C; homohalichondrin A, B, C; eribulin) andintermediates in the synthesis thereof.

In one aspect, the present invention provides a method of preparing acompound of Formula (I):

or a salt thereof,the method comprising coupling a compound of Formula (i):

or a salt thereof,with an aldehyde of Formula (ii):

in the presence of a chromium catalyst and optionally one or morecatalysts;wherein

R¹ is optionally substituted alkyl, optionally substituted alkenyl,optionally substituted alkynyl, optionally substituted carbocyclyl,optionally substituted heterocyclyl, optionally substituted aryl, oroptionally substituted heteroaryl;

R² is —OR⁵;

R⁵ is optionally substituted alkyl, or an oxygen protecting group;

R³ is —OR⁶;

R⁶ is optionally substituted alkyl, or an oxygen protecting group;

or R² and R³ are taken together to form ═O;

or R⁵ and R⁶ are taken together with the intervening atoms to form anoptionally substituted heterocyclic ring;

R⁴ is optionally substituted alkyl, optionally substituted alkenyl,optionally substituted alkynyl, optionally substituted carbocyclyl,optionally substituted heterocyclyl, optionally substituted aryl, oroptionally substituted heteroaryl;

R⁷ is halogen; and

L is optionally substituted ethenylene or ethynylene.

Since a hydroxyl group is generated in the coupling product of Formula(I), a chiral center can be introduced in the process. In someembodiments, the provided coupling method is a catalytic asymmetriccoupling between a compound of Formula (i) and an aldehyde of Formula(ii) to provide a compound of Formula (I^(a)):

or a salt thereof. In some embodiments, the provided coupling method isa catalytic asymmetric coupling between a compound of Formula (i) and analdehyde of Formula (ii) to provide a compound of Formula (I^(a)):

or a salt thereof.

In certain embodiments, the provided coupling reaction between thecompound of Formula (i) and the aldehyde of Formula (ii) is selectivefor halo-enone, halo-enone ketal, halo-acetylenic ketone, orhalo-acetylenic ketal, over a halide attached to a sp³ hybridizedcarbon. A vinyl halide or a halide attached to a sp³ hybridized carboncan remain intact during the coupling reaction between a halo-enone,halo-enone ketal, halo-acetylenic enone, or halo-acetylenic ketal, withan aldehyde of Formula (ii). The vinyl halide moiety can be a portion ofthe compound of Formula (i), the aldehyde of Formula (ii), or anothercompound in the coupling reaction mixture. In certain embodiments, theprovided coupling reaction between the compound of Formula (i) and thealdehyde of Formula (ii) is selective for the halo-enone orhalo-acetylenic ketal over a halide attached to a sp³ hybridized carbon.In certain embodiments, the halide attached to a sp³ hybridized carbonis chloride. In certain embodiments, the halide attached to a sp³hybridized carbon is bromide. In certain embodiments, the halideattached to a sp³ hybridized carbon is iodide. In certain embodiments,the compound of Formula (i) comprises a halide attached to a sp³hybridized carbon, for example, in R¹. In certain embodiments, the stepof coupling is performed in the presence of another compound other thanthe compounds of Formulae (i) and (ii), wherein the another compoundcomprises a halide attached to a sp3 hybridized carbon.

In certain embodiments, the provided coupling reaction between thecompound of Formula (i) and the aldehyde of Formula (ii) is selectivefor halo-enone, halo-enone ketal, halo-acetylenic ketone, orhalo-acetylenic ketal over a vinyl halide. In certain embodiments, theprovided coupling reaction between the compound of Formula (i) and thealdehyde of Formula (ii) is selective for the halo-enone orhalo-acetylenic ketal over a vinyl halide. In certain embodiments, thecompound of Formula (i) comprises a vinyl halide moiety, for example, aspart of R¹. In certain embodiments, the step of coupling is performed inthe presence of another compound other than the compounds of Formulae(i) and (ii), wherein the other compound includes a vinyl halide moiety.In certain embodiments, the vinyl halide moiety is a vinyl iodidemoiety. In certain embodiments, the vinyl halide is a vinyl bromidemoiety. In certain embodiments, the vinyl halide is a vinyl chloridemoiety. In certain embodiments, the vinyl halide moiety is a vinyliodide moiety in the compound of Formula (i). In certain embodiments,the vinyl halide is a vinyl bromide moiety in the compound of Formula(i). In certain embodiments, the vinyl halide is a vinyl chloride moietyin the compound of Formula (i). In certain embodiments, the vinyl halidemoiety is a vinyl iodide moiety in R¹ of the compound of Formula (i). Incertain embodiments, the vinyl halide is a vinyl bromide moiety in R¹ ofthe compound of Formula (i). In certain embodiments, the vinyl halide isa vinyl chloride moiety in R¹ of the compound of Formula (i). In certainembodiments, the vinyl halide moiety is a vinyl iodide moiety in thealdehyde of Formula (ii). In certain embodiments, the vinyl halide is avinyl bromide moiety in the aldehyde of Formula (ii). In certainembodiments, the vinyl halide is a vinyl chloride moiety in the aldehydeof Formula (ii). In certain embodiments, the vinyl halide moiety is avinyl iodide moiety in another compound other than the compounds ofFormulae (i) and (ii) in the coupling reaction mixture. In certainembodiments, the vinyl halide is a vinyl bromide moiety in anothercompound other than the compounds of Formulae (i) and (ii) in thecoupling reaction mixture. In certain embodiments, the vinyl halide is avinyl chloride moiety in another compound other than the compounds ofFormulae (i) and (ii) in the coupling reaction mixture.

As generally defined herein, R¹ is optionally substituted alkyl,optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted carbocyclyl, optionally substituted heterocyclyl,optionally substituted aryl, or optionally substituted heteroaryl. Incertain embodiments, R¹ is optionally substituted alkyl. In certainembodiments, R¹ is unsubstituted alkyl. In certain embodiments, R¹ ismethyl or ethyl. In certain embodiments, R¹ is n-C₇H₁₅. In certainembodiments, R¹ is substituted alkyl. In certain embodiments, R¹ isoptionally substituted alkoxylalkyl. In certain embodiments, R¹ isoptionally substituted alkenylalkyl. In certain embodiments, R¹ isunsubstituted alkenylalkyl. In certain embodiments, R¹ is substitutedalkenylalkyl. In certain embodiments, R¹ is optionally substitutedarylalkyl. In certain embodiments, R¹ is optionally substitutedphenylalkyl. In certain embodiments, R¹ is unsubstituted phenylalkyl. Incertain embodiments, R¹ is substituted phenylalkyl. In certainembodiments, R¹ is iodo-phenylalkyl. In certain embodiments, R¹ isp-iodo-phenylalkyl. In certain embodiments, R¹ is m-iodo-phenylalkyl. Incertain embodiments, R¹ is o-iodo-phenylalkyl.

In certain embodiments, R¹ comprises a halide attached to a sp³hybridized carbon. In certain embodiments, R¹ comprises a chlorideattached to a sp³ hybridized carbon. In certain embodiments, R¹comprises a bromide attached to a sp³ hybridized carbon. In certainembodiments, R¹ comprises an iodide attached to a sp³ hybridized carbon.

In certain embodiments, R¹ comprises a vinyl halide moiety. In certainembodiments, R¹ comprises a vinyl iodide moiety. In certain embodiments,R¹ comprises a vinyl bromide moiety. In certain embodiments, R¹comprises a vinyl chloride moiety.

As generally used herein, a vinyl halide is a compound of Formula (VY):

or a salt thereof,wherein

each of R^(VY1), R^(VY2), and R^(VY3) is independently hydrogen,optionally substituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted carbocyclyl, optionallysubstituted heterocyclyl, optionally substituted aryl, or optionallysubstituted heteroaryl; and

X^(V) is halogen.

As generally used herein, a vinyl halide is a vinyl iodide of Formula(VY-1):

or a salt thereof, wherein R^(VY1), R^(VY2), and R^(VY3) are as definedherein.

In certain embodiments, R¹ comprises a vinyl halide moiety and is ofFormula (F-1):

wherein

each of R^(1a), R^(1b), and R^(1c) is independently hydrogen, halogen,optionally substituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted carbocyclyl, optionallysubstituted heterocyclyl, optionally substituted aryl, or optionallysubstituted heteroaryl;

each instance of R^(1d) is independently hydrogen, halogen, optionallysubstituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted carbocyclyl, optionallysubstituted heterocyclyl, optionally substituted aryl, or optionallysubstituted heteroaryl; and

n is an integer between 1 to 10, inclusive.

As generally defined herein, R^(1a) is independently hydrogen, halogen,optionally substituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted carbocyclyl, optionallysubstituted heterocyclyl, optionally substituted aryl, or optionallysubstituted heteroaryl. In certain embodiments, R^(1a) is hydrogen. Incertain embodiments, R^(1a) is halogen. In certain embodiments, R^(1a)is iodide. In certain embodiments, R^(1a) is bromide. In certainembodiments, R^(1a) is chloride. In certain embodiments, R^(1a) isoptionally substituted alkyl. In certain embodiments, R^(1a) isunsubstituted alkyl. In certain embodiments, R^(1a) is methyl or ethyl.In certain embodiments, R^(1a) is substituted alkyl.

As generally defined herein, R^(1b) is independently hydrogen, halogen,optionally substituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted carbocyclyl, optionallysubstituted heterocyclyl, optionally substituted aryl, or optionallysubstituted heteroaryl. In certain embodiments, R^(1b) is hydrogen. Incertain embodiments, R^(1b) is halogen. In certain embodiments, R^(1b)is iodide. In certain embodiments, R^(1b) is bromide. In certainembodiments, R^(1b) is chloride. In certain embodiments, R^(1b) isoptionally substituted alkyl. In certain embodiments, R^(1b) isunsubstituted alkyl. In certain embodiments, R^(1b) is methyl or ethyl.In certain embodiments, R^(1b) is substituted alkyl.

As generally defined herein, R^(1c) is independently hydrogen, halogen,optionally substituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted carbocyclyl, optionallysubstituted heterocyclyl, optionally substituted aryl, or optionallysubstituted heteroaryl. In certain embodiments, R^(1c) is hydrogen. Incertain embodiments, R^(1c) is halogen. In certain embodiments, R^(1c)is iodide. In certain embodiments, R^(1c) is bromide. In certainembodiments, R^(1c) is chloride. In certain embodiments, R^(1c) isoptionally substituted alkyl. In certain embodiments, R^(1c) isunsubstituted alkyl. In certain embodiments, R^(1c) is methyl or ethyl.In certain embodiments, R^(1c) is substituted alkyl.

In certain embodiments, R^(1a) is halogen; and R^(1b) and R^(1c) arehydrogen. In certain embodiments, R^(1a) is iodide; and R^(1b) andR^(1c) are hydrogen. In certain embodiments, R^(1a) is bromide; andR^(1b) and R^(1c) are hydrogen.

As generally defined herein, each instance of R^(1d) is independentlyhydrogen, halogen, optionally substituted alkyl, optionally substitutedalkenyl, optionally substituted alkynyl, optionally substitutedcarbocyclyl, optionally substituted heterocyclyl, optionally substitutedaryl, or optionally substituted heteroaryl. In certain embodiments, atleast one instance of R^(1d) is hydrogen. In certain embodiments, eachinstance of R^(1d) is hydrogen. In certain embodiments, at least oneinstance of R^(1d) is halogen. In certain embodiments, at least oneinstance of R^(1d) is iodide. In certain embodiments, at least oneinstance of R^(1d) is bromide. In certain embodiments, at least oneinstance of R^(1d) is chloride. In certain embodiments, at least oneinstance of R^(1d) is optionally substituted alkyl. In certainembodiments, at least one instance of R^(1d) is unsubstituted alkyl. Incertain embodiments, at least one instance of R^(1d) is methyl or ethyl.In certain embodiments, at least one instance of R^(1d) is substitutedalkyl.

In certain embodiments, n is 1. In certain embodiments, n is 2. Incertain embodiments, n is 3. In certain embodiments, n is 4. In certainembodiments, n is 5. In certain embodiments, n is 6.

In certain embodiments, n is 4, and at least one instance of R^(1d) ishalogen. In certain embodiments, n is 4, and one instance of R^(1d) ishalogen. In certain embodiments, n is 4, and one instance of R^(1d) ischloride.

As generally defined herein, R² is —OR⁵, wherein R⁵ is optionallysubstituted alkyl or an oxygen protecting group. In certain embodiments,R⁵ is optionally substituted alkyl. In certain embodiments, R⁵ isunsubstituted alkyl (e.g. methyl or ethyl). In certain embodiments, R⁵is substituted alkyl. In certain embodiments, R⁵ is an oxygen protectinggroup.

As generally defined herein, R³ is —OR⁶, wherein R⁶ is optionallysubstituted alkyl or an oxygen protecting group. In certain embodiments,R⁶ is optionally substituted alkyl. In certain embodiments, R⁶ isunsubstituted alkyl (e.g. methyl or ethyl). In certain embodiments, R⁶is substituted alkyl. In certain embodiments, R⁶ is an oxygen protectinggroup.

In certain embodiments, R² and R³ are taken together to form ═O. Incertain embodiments, the compound of Formula (I) is of one of theformulae:

or a salt thereof; and the compound of Formula (i) is of the formula:

or a salt thereof.

In certain embodiments, R² is —OR⁵; R³ is —OR⁶; and R⁵ and R⁶ are eachindependently oxygen protecting groups. In certain embodiments, thecompound of Formula (I) is of the formula:

or a salt thereof; and the compound of Formula (i) is of the formula:

or a salt thereof.

As generally defined herein, R⁴ is optionally substituted alkyl,optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted carbocyclyl, optionally substituted heterocyclyl,optionally substituted aryl, or optionally substituted heteroaryl. Incertain embodiments, R⁴ is optionally substituted alkyl. In certainembodiments, R⁴ is unsubstituted alkyl. In certain embodiments, R⁴ ismethyl or ethyl. In certain embodiments, R⁴ is substituted alkyl. Incertain embodiments, R⁴ is optionally substituted alkoxylalkyl. Incertain embodiments, R⁴ is optionally substituted alkenylalkyl. Incertain embodiments, R⁴ is unsubstituted alkenylalkyl. In certainembodiments, R⁴ is substituted alkenylalkyl. In certain embodiments, R⁴is optionally substituted arylalkyl. In certain embodiments, R⁴ isoptionally substituted phenylalkyl. In certain embodiments, R⁴ isunsubstituted phenylalkyl. In certain embodiments, R⁴ is substitutedphenylalkyl. In certain embodiments, R⁴ is optionally substitutedheteroarylalkyl. In certain embodiments, R⁴ is optionally substitutedheterocyclylalkyl. In certain embodiments, R⁴ is optionally substitutedcarbocyclylalkyl. In certain embodiments, R⁴ is optionally substitutedcarbocyclyl. In certain embodiments, R⁴ is optionally substitutedheterocyclyl. In certain embodiments, R⁴ is optionally substituted aryl.In certain embodiments, R⁴ is optionally substituted phenyl. In certainembodiments, R⁴ is optionally substituted heteroaryl. In certainembodiments, R⁴ is optionally substituted furanyl, thiophenyl, orpyrrolyl.

As generally defined herein, L is optionally substituted ethenylene orethynylene. In certain embodiments, L is optionally substitutedethenylene. In certain embodiments, L is unsubstituted ethenylene. Incertain embodiments, L is substituted ethenylene. In certainembodiments, L is optionally substituted trans-ethenylene. In certainembodiments, L is unsubstituted trans-ethenylene. In certainembodiments, L is substituted trans-ethenylene. In certain embodiments,L is optionally substituted cis-ethenylene. In certain embodiments, L isunsubstituted cis-ethenylene. In certain embodiments, L is substitutedcis-ethenylene. In certain embodiments, L is ethynylene. L beingoptionally substituted ethenylene

In certain embodiments of the provided coupling method between acompound of Formula (i) and the aldehyde of Formula (ii), the compoundof Formula (i) is of Formula (i-a):

or a salt thereof, wherein R¹, R², R³, and R⁷ are as defined herein, andeach of R⁸ and R⁹ is independently hydrogen or optionally substitutedalkyl.

In certain embodiments of the provided coupling method between acompound of Formula (i) and the aldehyde of Formula (ii), the compoundof Formula (i) is of Formula (i-a):

or a salt thereof, wherein R¹, R², R³, and R⁷ are as defined herein, andeach of R⁸ and R⁹ is independently hydrogen or optionally substitutedalkyl.

In certain embodiments, R⁸ is hydrogen. In certain embodiments, R⁸ isoptionally substituted alkyl. In certain embodiments, R⁸ isunsubstituted alkyl. In certain embodiments, R⁸ is methyl or ethyl. Incertain embodiments, R⁸ is substituted alkyl.

In certain embodiments, R⁹ is hydrogen. In certain embodiments, R⁹ isoptionally substituted alkyl. In certain embodiments, R⁹ isunsubstituted alkyl. In certain embodiments, R⁹ is methyl or ethyl. Incertain embodiments, R⁹ is substituted alkyl.

In certain embodiments, the coupling step is between a compound ofFormula (i-a) and an aldehyde of Formula (ii) to yield a compound of oneof the following formulae:

and salts thereof. In certain embodiments, the compound of Formula (I)is of Formula (I-a):

In certain embodiments, the compound of Formula (I) is of Formula(I-a-2):

In certain embodiments, the coupling step is between a compound ofFormula (i-a′) and an aldehyde of Formula (ii) to yield a compound ofone of the following formulae:

and salts thereof. In certain embodiments, the coupling step is betweena compound of Formula (i-a′) and an aldehyde of Formula (ii) to yield acompound of one of the following formulae:

In certain embodiments, the compound of Formula (i) is of Formula(i-a-1):

or a salt thereof; and the compound of Formula (I) is of Formula (I-a-1)

or a salt thereof; wherein R¹, R⁷, and R⁴ are as defined herein.

In some embodiments, the coupling product of Formulae (I)-(I-a-1) arestable enough to isolate and characterize. In some embodiments, thecoupling product of Formula (I)-(I-a-1) cyclizes to form an optionallysubstituted furan of Formula (FU-1):

or a salt thereof,wherein R¹ and R⁴ are as defined herein; and

each of R^(FU1) and R^(FU2) is independently hydrogen, optionallysubstituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted carbocyclyl, optionallysubstituted heterocyclyl, optionally substituted aryl, or optionallysubstituted heteroaryl.

In certain embodiments, the step of cyclizing occurs in situ (i.e. inthe reaction mixture without isolation). In certain embodiments, thestep of cyclizing occurs upon addition of an acid. In certainembodiments, the acid is a Lewis acid. In certain embodiments, the acidis a Brønsted acid. In certain embodiments, the acid is one or moreselected from the group consisting of p-toluenesulfonic acid (PTSA),p-toluenesulfonic acid (p-TSA), or camphorsulfonic acid (CSA),pyridinium p-toluenesulfonate (PPTS), or sulfonic acid exchange resin(Amberlyst, Dowex). In certain embodiments, the acid isp-toluenesulfonic acid (p-TSA) or camphorsulfonic acid (CSA).

In certain embodiments, the provided coupling method is applied tosynthesis of the C1-C19 building block of halichondrins and analogsthereof. In certain embodiments, the provided coupling method is appliedto the synthesis of the C1-C19 building block of halichondrin B.

In certain embodiments, the compound of Formula (i-a-1) is of Formula(i-a-3):

or a salt thereof; the aldehyde of Formula (ii) is of Formula (ii-a):

or a salt thereof; and the compound of Formula (I) is of Formula(I-a-3):

or a salt thereof,wherein

R^(1a) and R^(1d) are as defined herein,

R^(4a) is CO₂R^(4d), wherein R^(4d) is hydrogen, optionally substitutedalkyl, or an oxygen protecting group; and

R^(4b) and R^(4c) are each independently substituted or unsubstitutedalkyl, or an oxygen protecting group; or R^(4b) and R^(4c) are takenwith the intervening oxygen atoms to form an optionally substitutedheterocyclic ring.

As generally defined herein, R^(4a) is —CO₂R^(4d), wherein R^(4d) ishydrogen, optionally substituted alkyl, or an oxygen protecting group.In certain embodiments, R^(4d) is hydrogen. In certain embodiments,R^(4d) is optionally substituted alkyl. In certain embodiments, R^(4d)is unsubstituted alkyl. In certain embodiments, R^(4d) is methyl orethyl. In certain embodiments, R^(4d) is substituted alkyl. In certainembodiments, R^(4d) is an oxygen protecting group.

In certain embodiments, R^(4b) is optionally substituted alkyl. Incertain embodiments, R^(4b) is unsubstituted alkyl. In certainembodiments, R^(4b) is methyl or ethyl. In certain embodiments, R^(4b)is an oxygen protecting group. In certain embodiments, R^(4b) is a silylprotecting group. In certain embodiments, R^(4b) is a trialkyl silylprotecting group. In certain embodiments, R^(4b) is at-butyldimethylsilyl protecting group. In certain embodiments, R^(4b) isa trimethylsilyl protecting group. In certain embodiments, R^(4b) is atriethylsilyl protecting group. In certain embodiments, R^(4b) is at-butyldiphenylsilyl protecting group. In certain embodiments, R^(4b) isa triisopropylsilyl protecting group. In certain embodiments, R^(4b) isa benzylic protecting group. In certain embodiments, R^(4b) is ap-methoxybenzyl protecting group. In certain embodiments, R^(4b) is anacyl protecting group. In certain embodiments, R^(4b) is an acetylprotecting group. In certain embodiments, R^(4b) is a benzoyl protectinggroup. In certain embodiments, R^(4b) is a p-nitro benzoyl protectinggroup. In certain embodiments, R^(4b) is a pivaloyl protecting group. Incertain embodiments, R^(4b) is a t-butyl carbonate (BOC) protectinggroup. In certain embodiments, R^(4b) is an acetal protecting group. Incertain embodiments, R^(4b) is a tetrahydropyranyl protecting group. Incertain embodiments, R^(4b) is an alkoxyalkyl protecting group. Incertain embodiments, R^(4b) is an ethoxyethyl protecting group.

In certain embodiments, R^(4c) is optionally substituted alkyl. Incertain embodiments, R^(4c) is unsubstituted alkyl. In certainembodiments, R^(4c) is methyl or ethyl. In certain embodiments, R^(4c)is an oxygen protecting group. In certain embodiments, R^(4c) is a silylprotecting group. In certain embodiments, R^(4c) is a trialkyl silylprotecting group. In certain embodiments, R^(4c) is at-butyldimethylsilyl (TBS) protecting group. In certain embodiments,R^(4c) is a trimethylsilyl protecting group. In certain embodiments,R^(4c) is a triethylsilyl protecting group. In certain embodiments,R^(4c) is a t-butyldiphenylsilyl protecting group. In certainembodiments, R^(4c) is a triisopropylsilyl protecting group. In certainembodiments, R^(4c) is a benzylic protecting group. In certainembodiments, R^(4c) is a p-methoxybenzyl protecting group. In certainembodiments, R^(4c) is an acyl protecting group. In certain embodiments,R^(4c) is an acetyl protecting group. In certain embodiments, R^(4c) isa benzoyl protecting group. In certain embodiments, R^(4c) is a p-nitrobenzoyl protecting group. In certain embodiments, R^(4c) is a pivaloylprotecting group. In certain embodiments, R^(4c) is a t-butyl carbonate(BOC) protecting group. In certain embodiments, R^(4c) is an acetalprotecting group. In certain embodiments, R^(4c) is a tetrahydropyranylprotecting group. In certain embodiments, R^(4c) is an alkoxyalkylprotecting group. In certain embodiments, R^(4c) is an ethoxyethylprotecting group.

In certain embodiments, R^(4b) and R^(4c) are independently an oxygenprotecting group. In certain embodiments, R^(4b) and R^(4c) are thesame. In certain embodiments, R^(4b) and R^(4c) are different. Incertain embodiments, R^(4b) and R^(4c) are independently a silylprotecting group. In certain embodiments, R^(4b) and R^(4c) are at-butyldimethylsilyl protecting group.

In certain embodiments, R^(4b) and R^(4c) are taken with the interveningoxygen atoms to form an optionally substituted heterocyclic ring. Incertain embodiments, R^(4b) and R^(4c) are taken with the interveningoxygen atoms to form an optionally substituted monocyclic heterocyclicring. In certain embodiments, R^(4b) and R^(4c) are taken with theintervening oxygen atoms to form an optionally substituted bicyclicheterocyclic ring. In certain embodiments, R^(4b) and R^(4c) are takenwith the intervening oxygen atoms to form an optionally substitutedbicyclic heterocyclic ring of formula:

In certain embodiments, the compound of Formula (ii-a) is of Formula(ii-a-1):

or a salt thereof. In certain embodiments, the compound of Formula(I-a-3) is of the Formula (I-a-3-i):

or a salt thereof.

In certain embodiments, the coupling reaction between the compounds ofFormula (i-a-3) and Formula (ii-a) is achieved with highregioselectivity of the bromo-enone over R^(1a) and highstereoselectivity with one or more chiral catalyst ligands (see theCatalystic Condition Section). The compounds of Formulae (I-a-3) and(I-a-3-i) provide an efficient synthesis of the C1-C19 building block ofhalichondrin B.

In one aspect, provided herein is a method of preparing a compound ofFormula (I-a-4):

or a salt thereof, comprising cyclizing a compound of Formula (I-a-5):

or a salt thereof, wherein R^(1a), R^(1d), R^(4a), R^(4b), and R^(4c)are as defined herein; and R^(PA) is optionally substituted alkyl or anoxygen protecting group.

In certain embodiments, the step of cyclizing comprises deprotecting thecompound of Formula (I-a-5), i.e., converting R^(4b) and R^(4c) tohydrogen.

In certain embodiments, the steps of cyclizing further comprisingequilibrating the deprotected compound of Formula (I-a-5) with one ormore bases. The equilibrating step isomerizes the C12 chiral center (seeFIG. 15). It is to be understood that any organic and inorgance base isapplicable as long as the base does not interfere with any functionalgroups of the deprotected compound of Formula (I-a-5). In certainembodiments, the base is one or more organic or inorganic bases. Incertain embodiments, the base is one organic or inorganic base. Incertain embodiments, the base is sodium carbonate,1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), or tetramethylguanidine Incertain embodiments, the base is a combination of two or more organic orinorganic bases. In certain embodiments, the bases are1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and tetramethylguanidine.

In certain embodiments, the step of cyclizing further comprisingcontacting the equilibrating reaction mixture with an acid. In certainembodiments, the acid is a Lewis acid. In certain embodiments, the acidis a Brønsted acid. In certain embodiments, the acid is one or moreselected from the group consisting of p-toluenesulfonic acid (PTSA),p-toluenesulfonic acid (p-TSA), camphorsulfonic acid (CSA), pyridiniump-toluenesulfonate (PPTS), and sulfonic acid exchange resin (Amberlyst,Dowex). In certain embodiments, the acid is pyridiniump-toluenesulfonate (PPTS).

In certain embodiments, the steps of cyclizing further comprisescontacting the equilibration reaction mixture with one or moreion-exchange resins. In certain embodiments, the ion-exchange resins arepolymer-bound guanidine and polymer-bound pyridinium p-toluenesulfonate(PPTS).

In certain embodiments, the step of cyclizing further comprisingcontacting the equilibrating reaction mixture with an acid in anion-exchange resin device. In certain embodiments, the ion-exchangeresin device comprises a first column with basic ion exchange resins anda second column with acidic ion exchange resins. In certain embodiments,the ion-exchange resin device comprises a first column with basic ionexchange resins and a dehydrating reagent (e.g., 4 Å molecular sieves);and a second column with acidic ion exchange resins and a dehydratingreagent (e.g., 4 Å molecular sieves). In certain embodiments, theion-exchange resin device is as shown in FIG. 2.

In certain embodiments, the provided method of synthesizing the C1-C19building block of halichondrin B further comprises the step ofprotecting a compound of Formula (I-a-3):

or a salt thereof, to yield a compound of Formula (I-a-5):

or a salt thereof, wherein R^(1a), R^(1d), R^(4a), R^(4b), R^(4c), andR^(P1) are as defined herein.

In certain embodiments, R^(PA) is optionally substituted alkyl. Incertain embodiments, R^(PA) is unsubstituted alkyl. In certainembodiments, R^(PA) is methyl or ethyl. In certain embodiments, R^(PA)is an oxygen protecting group. In certain embodiments, R^(PA) is a silylprotecting group. In certain embodiments, R^(PA) is a trialkyl silylprotecting group. In certain embodiments, R^(PA) is at-butyldimethylsilyl (TBS) protecting group. In certain embodiments,R^(PA) is a trimethylsilyl protecting group. In certain embodiments,R^(PA) is a triethylsilyl protecting group. In certain embodiments,R^(PA) is a t-butyldiphenylsilyl protecting group. In certainembodiments, R^(PA) is a triisopropylsilyl protecting group. In certainembodiments, R^(PA) is a benzylic protecting group. In certainembodiments, R^(PA) is a p-methoxybenzyl protecting group. In certainembodiments, R^(PA) is an acyl protecting group. In certain embodiments,R^(PA) is an acetyl protecting group. In certain embodiments, R^(PA) isa benzoyl protecting group. In certain embodiments, R^(PA) is a p-nitrobenzoyl protecting group. In certain embodiments, R^(PA) is a pivaloylprotecting group. In certain embodiments, R^(PA) is a t-butyl carbonate(BOC) protecting group. In certain embodiments, R^(PA) is an acetalprotecting group. In certain embodiments, R^(PA) is a tetrahydropyranylprotecting group. In certain embodiments, R^(PA) is an alkoxyalkylprotecting group. In certain embodiments, R^(PA) is an ethoxyethylprotecting group.

In certain embodiments, R^(4b) and R^(4c) are independently a silylprotecting group; and R^(PA) is an acyl protecting group. In certainembodiments, R^(4b) and R^(4c) are a t-butyldimethylsilyl protectinggroup; and R^(PA) is an acyl protecting group. In certain embodiments,R^(4b) and R^(4c) are a t-butyldimethylsilyl protecting group; andR^(PA) is an optionally substituted benzoylic protecting group. Incertain embodiments, R^(4b) and R^(4c) are t-butyldimethylsilylprotecting groups; and R^(PA) is an optionally substitutedp-NO₂-benzoylic protecting group.

In certain embodiments, R^(4b) and R^(4c) are taken with the interveningoxygen atoms to form an optionally substituted heterocyclic ring andR^(PA) is an acyl protecting group an acyl protecting group. In certainembodiments, R^(4b) and R^(4c) are taken with the intervening oxygenatoms to form an optionally substituted monocyclic heterocyclic ring andR^(PA) is an acyl protecting group an acyl protecting group. In certainembodiments, R^(4b) and R^(4c) are taken with the intervening oxygenatoms to form an optionally substituted bicyclic heterocyclic ring ofthe formula:

and R^(PA) is an optionally substituted benzoylic protecting group. Incertain embodiments, R^(4b) and R^(4c) are taken with the interveningoxygen atoms to form an optionally substituted bicyclic heterocyclicring of the formula:

and R^(PA) is an optionally substituted p-NO₂-benzoylic protectinggroup.L being Ethynylene

In certain embodiments of the provided coupling method between thecompound of Formula (i) and the aldehyde of Formula (ii), the compoundof Formula (i) is of Formula (i-b):

or a salt thereof, and the compound of Formula (I) is of Formula (I-b):

or a salt thereof, wherein R¹, R², R³, R⁴, and R⁷ are as defined herein.

In certain embodiments, the compound of Formula (i) is of Formula(i-b-1):

or a salt thereof, and the compound of Formula (I) is of Formula (I-b-1)

or a salt thereof, wherein R¹, R⁴, and R⁷ are as defined herein.

In certain embodiments, the compound of Formula (i) is of Formula(i-b-2):

or a salt thereof, and the compound of Formula (I) is of Formula(I-b-2):

or a salt thereof, wherein R¹, R⁴, and R⁷ are as defined herein.

In certain embodiments, the compound of Formula (i) is of Formula(i-b-3):

or a salt thereof, and the compound of Formula (I) is of Formula (I-b-3)

or a salt thereof, wherein R¹, R⁴, and R⁷ are as defined herein.

In certain embodiments, the compound of Formula (i) is of Formula(i-b-4):

or a salt thereof, and the compound of Formula (I) is of Formula(I-b-4):

or a salt thereof, wherein R¹, R⁴, and R⁷ are as defined herein.

Methods for Preparing C1-C19 Building Block of Halichondrins

In certain embodiments, the provided coupling method can be applied tosynthesizing the C1-C19 building blocks of halichondrin A, B, and C, andanalogs thereof (e.g., norhalichondrin A, B, C; homohalichondrin A, B,C). The synthesis involves formation of an intermediate of Formula(I-b-5). In certain embodiments, the compound of Formula (i) is ofFormula (i-b-5):

or a salt thereof, and thealdehyde of Formula (ii) is of Formula (ii-a):

or a salt thereof, and the compound of Formula (I) is of Formula(I-b-5):

(I-b-5) or a salt thereof, wherein R^(1a), R^(1d), R^(4a), R^(4b), andR^(4c) are as defined herein.

In another aspect of the present invention, provided herein is a methodof synthesizing the C1-C19 building block of halichondrin C and analogs(e.g., norhalichondrin C, homohalichondrin C). In certain embodiments,provided herein is a method of preparing a compound of Formula (I-b-6):

or a salt thereof, comprising contacting a compound of Formula (I-b-7):

or a salt thereof,with a Lewis acid and an alcohol, wherein R^(1a), R^(1d), R^(4a),R^(4b), and R^(4c) are as defined herein, and R¹⁰ is hydrogen,optionally substituted alkyl, or an oxygen protecting group.

In certain embodiments, R¹⁰ is hydrogen. In certain embodiments, R¹⁰ isoptionally substituted alkyl. In certain embodiments, R¹⁰ isunsubstituted alkyl. In certain embodiments, R¹⁰ is methyl or ethyl. Incertain embodiments, R¹⁰ is substituted alkyl. In certain embodiments,R¹⁰ is optionally substituted alkenylalkyl. In certain embodiments, R¹⁰is unsubstituted alkenylalkyl. In certain embodiments, R¹⁰ isCH₂═CHCH₂—. In certain embodiments, R¹⁰ is an oxygen protecting group.In certain embodiments, R¹⁰ is a silyl protecting group. In certainembodiments, R¹⁰ is an acetyl protecting group.

As generally defined herein, the Lewis acid is a chemical species thatreacts with a Lewis base to form a Lewis adduct. In certain embodiments,the Lewis acid is a metal salt that can accept a pair of electrons. Incertain embodiments, the Lewis acid is a metal halide. In certainembodiments, the Lewis acid is a metal acetate. In certain embodiments,the Lewis acid is a metal triflate. In certain embodiments, the Lewisacid is a transition metal halide. In certain embodiments, the Lewisacid is a transition metal acetate. In certain embodiments, the Lewisacid is a transition metal triflate. In certain embodiments, the Lewisacid is Sc(OTf)₃, Ln(OTf)₃, Yb(OTf)₃, Lu(OTf)₃, Hf(OTf)₄, CuOTf. Incertain embodiments, the Lewis acid is a hafnium(IV) salt. In certainembodiments, the Lewis acid is Hf(OTf)₄.

In certain embodiments, the alcohol is an optionally substituted alkylalcohol. In certain embodiments, the alcohol is an optionallysubstituted alkenylalkyl alcohol. In certain embodiments, the alcohol isan unsubstituted alkenylalkyl alcohol. In certain embodiments, thealcohol is CH₂═CHCH₂OH.

In certain embodiments of synthesizing the C1-C19 building block ofhalichondrin C and analogs, the step of contacting the compound ofFormula (I-b-7) with a Lewis acid and an alcohol further comprising thestep of deprotecting a compound of Formula (I-b-8):

or a salt thereof, to yield a compound of Formula (I-b-7):

or a salt thereof, wherein R^(1a), R^(1d), R^(4a), R^(4b) and R^(4c) areas defined herein. In certain embodiments, this step of deprotectingcomprises converting the protecting groups at R^(4b) and R^(4c) tohydrogen. In certain embodiments, the protecting groups at R^(4b) andR^(4c) are silyl protecting groups. In certain embodiments, this step ofdeprotecting is performed in the presence of a source of fluoride. Incertain embodiments, the step of deprotecting is performed in thepresence of HF-pyridine. In certain embodiments, the step ofdeprotecting is performed in the presence of HF-pyridine followed bytreatment with a base. In certain embodiments, the step of deprotectingis performed in the presence of HF-pyridine followed by treatment withan organic base. In certain embodiments, the step of deprotecting isperformed in the presence of HF-pyridine followed by treatment withEt₃N.

In certain embodiments of synthesizing the C1-C19 building block ofhalichondrin C and analogs, the method further comprises the step ofdeprotecting a compound of Formula (I-b-5):

or a salt thereof, to yield a compound of Formula (I-b-8):

or a salt thereof, wherein R^(1a), R^(1d), R^(4a), R^(4b), and R^(4c)are as defined herein. In certain embodiments, this step of deprotectingcomprises converting the ketal of the compound of Formula (I-b-5) to aketone of the compound of Formula (I-b-8). In certain embodiments, thestep of deprotecting is performed in the presence of an acid. In certainembodiments, this step of deprotecting is performed in the presence of aBøonsted acid (i.e., a source of H⁺).

In another aspect of the present invention, provided herein is a methodof synthesizing the C1-C19 building block of halichondrin B and analogs(e.g., norhalichondrin B, homohalichondrin B). In certain embodiments,provided herein is a method of preparing a compound of Formula (I-a-4):

or a salt thereof, comprising the steps of deprotecting a compound ofFormula (I-b-10):

or a salt thereof, followed by cyclizing the deprotected compound,wherein R^(1a), R^(1d), R^(4a), and R^(4b) are as defined herein. Incertain embodiments, the step of cyclizing comprises contacting thecompound of Formula (I-b-10) with an acid. In certain embodiments, theacid in the step of cyclizing is a Lewis acid. In certain embodiments,the acid in the step of cyclizing is a Brønsted acid. In certainembodiments, the acid in the step of cyclizing is an organic acid. Incertain embodiments, the acid is one or more selected from the groupconsisting of p-toluenesulfonic acid (PTSA), p-toluenesulfonic acid(p-TSA), or camphorsulfonic acid (CSA), pyridinium p-toluenesulfonate(PPTS), or sulfonic acid exchange resin (Amberlyst, Dowex). In certainembodiments, the acid is p-toluenesulfonic acid (p-TSA) orcamphorsulfonic acid (CSA). In certain embodiments, the acid in the stepof cyclizing is pyridinium p-toluenesulfonate (PPTS) orp-toluenesulfonic acid (p-TSA). In certain embodiments, the step ofcyclizing comprises contacting the compound of Formula (I-b-10) with anion-exchange resin. In certain embodiments, the ion-exchange resin is anacidic polymer-bound resin. In certain embodiments, the ion-exchangeresin is a polymer-bound PPTS.

In certain embodiments, the step of cyclizing further comprisingcontacting the equilibrating reaction mixture with an acid in anion-exchange resin device. In certain embodiments, the ion-exchangeresin device comprises a first column with basic ion exchange resins anda second column with acidic ion exchange resins. In certain embodiments,the ion-exchange resin device comprises a first column with basic ionexchange resins and a dehydrating reagent (e.g., 4 Å molecular sieves);and a second column with acidic ion exchange resins and a dehydratingreagent (e.g., 4 Å molecular sieves). In certain embodiments, theion-exchange resin device is as shown in FIG. 2.

In certain embodiments of synthesizing the C1-C19 building block ofhalichondrin B and analogs, the method further comprises the step ofreducing a compound of Formula (I-b-11):

or a salt thereof, to yield a compound of Formula (I-b-10):

or a salt thereof, wherein R^(1a), R^(1d), R^(4a), and R^(4b) are asdefined herein. In certain embodiments, the step of reducing isperformed in the presence of a source of hydride. In certainembodiments, the source of hydride is one or more reagents selected fromthe group of consisting of lithium hydrides, copper hydrides, and boronhydrides. In certain embodiments, the source of hydride is a boronhydride. In certain embodiments, the source of hydride is (Mc)₄NBH(OAc).

In certain embodiments of synthesizing the C1-C19 building block ofhalichondrin B and analogs, the method further comprises the step ofdeprotecting a compound of Formula I-b-8):

or a salt thereof, to yield a compound of Formula (I-b-11):

or a salt thereof, wherein R^(1a), R^(1d), R^(4a), R^(4b), and R^(4c)are as defined herein. In certain embodiments, the step of deprotectingis to convert the protecting group at R^(4c) to hydrogen. In certainembodiments, the step of deprotecting is to convert the protecting groupat R^(4c) to hydrogen, wherein both R^(4b) and R^(4c) are independentlysilyl protecting groups. In certain embodiments, this step ofdeprotecting is performed in the presence of a source of fluoride. Incertain embodiments, the step of deprotecting is performed in thepresence of HF-pyridine.

In another aspect of the present invention, provided herein is a methodof synthesizing the C1-C19 building block of halichondrin B and analogs.In certain embodiments, provided herein is a method of preparing acompound of Formula (I-a-4):

or a salt thereof, comprising the step of deprotecting a compound ofFormula (I-b-12):

or a salt thereof; and cyclizing the deprotected compound, whereinR^(1a), R^(1d), R^(4a), R^(4b), and R^(4c) are as defined herein. Incertain embodiments, the step of deprotecting is to convert theprotecting group at R^(4c) to hydrogen. In certain embodiments, the stepof deprotecting is to convert the protecting group at R^(4c) tohydrogen, wherein both R^(4b) and R^(4c) are independently silylprotecting groups. In certain embodiments, this step of deprotecting isperformed in the presence of a source of fluoride. In certainembodiments, the step of deprotecting is performed in the presence ofTBAF. In certain embodiments, the step of cyclizing comprises contactingthe reduced compound of Formula (I-b-12) with an organic acid. Incertain embodiments, the step of cyclizing comprises contacting thecompound of Formula (I-b-12) with an acid. In certain embodiments, theacid in the step of cyclizing is a Lewis acid. In certain embodiments,the acid in the step of cyclizing is a Brønsted acid. In certainembodiments, the acid in the step of cyclizing is pyridiniump-toluenesulfonate (PPTS) or p-toluenesulfonic acid (p-TSA). In certainembodiments, the step of cyclizing comprises contacting the compound ofFormula (I-b-12) with an ion-exchange resin. In certain embodiments, theion-exchange resin is an acidic polymer-bound resin. In certainembodiments, the ion-exchange resin is a polymer-bound PPTS.

In certain embodiments, the step of cyclizing further comprisingcontacting the equilibrating reaction mixture with an acid in anion-exchange resin device. In certain embodiments, the ion-exchangeresin device comprises a first column with basic ion exchange resins anda second column with acidic ion exchange resins. In certain embodiments,the ion-exchange resin device comprises a first column with basic ionexchange resins and a dehydrating reagent (e.g., 4 Å molecular sieves);and a second column with acidic ion exchange resins and a dehydratingreagent (e.g., 4 Å molecular sieves). In certain embodiments, theion-exchange resin device is as shown in FIG. 2.

In certain embodiments of synthesizing the C₁-C₁₉ building block ofhalichondrin B and analogs, the method further comprises the step ofreducing a compound of Formula (I-b-8):

or a salt thereof, to yield a compound of Formula (I-b-12):

or a salt thereof, wherein R^(1a), R^(1d), R^(4a), R^(4b), and R^(4c)are as defined herein. In certain embodiments, the step of reducing isperformed in the presence of a source of hydride. In certainembodiments, the source of hydride is one or more selected from thegroup of consisting of lithium hydrides, copper hydrides, and boronhydrides. In certain embodiments, the soured of hydride is a copperhydride. In certain embodiments, the soured of hydride is1,2-bis(diphenylphosphino)benzenecopper hydride ((BDP)CuH).

In anther aspect of the present invention, provided herein is a methodof synthesizing the C1-C19 building block of halichondrin A and analogs(e.g., norhalichondrin A, homohalichondrin A). In certain embodiments,provided herein is a method of preparing a compound of Formula (I-b-13):

or a salt thereof, comprising cyclizing a compound of Formula (I-b-14):

or a salt thereof, wherein R^(1a), R^(1d), R^(4a), R^(4b), and 10 are asdefined herein, and R¹¹ is hydrogen, optionally substituted alkyl, or anoxygen protecting group. In certain embodiments, the step of cyclizingcomprises oxidizing the compound of Formula (I-b-14). In certainembodiment, the step of oxidizing is to introduce the C13 hydroxylgroup. In certain embodiments, the step of oxidizing is performed in thepresence of an organic peroxide (e.g. a compound comprising an O—Obond). In certain embodiments, the step of oxidizing is performed in thepresence of dimethyldioxirane (DMDO). In certain embodiments, the stepof oxidizing further comprises contacting the oxidized compound ofFormula (I-b-14) with an acid. In certain embodiments, the acid is aLewis acid. In certain embodiments, the acid is a Brønsted acid. Incertain embodiments, the acid in the step of cyclizing is an organicacid. In certain embodiments, the acid is one or more selected from thegroup consisting of p-toluenesulfonic acid (PTSA), p-toluenesulfonicacid (p-TSA), or camphorsulfonic acid (CSA), pyridiniump-toluenesulfonate (PPTS), or sulfonic acid exchange resin (Amberlyst,Dowex). In certain embodiments, the acid is p-toluenesulfonic acid(p-TSA) or camphorsulfonic acid (CSA). In certain embodiments, the acidin the step of cyclizing is pyridinium p-toluenesulfonate (PPTS) orp-toluenesulfonic acid (p-TSA).

In certain embodiments, the step of cyclizing comprises contacting theoxidized compound of Formula (I-b-14) with PPTS. In certain embodiments,the step of cyclizing comprises contacting the oxidized compound ofFormula (I-b-14) with an ion-exchange resin. In certain embodiments, theion-exchange resin is an acidic polymer-bound resin. In certainembodiments, the ion-exchange resin is a polymer-bound PPTS.

In certain embodiments, the step of cyclizing further comprisingcontacting the equilibrating reaction mixture with an acid in anion-exchange resin device. In certain embodiments, the ion-exchangeresin device comprises a first column with basic ion exchange resins anda second column with acidic ion exchange resins. In certain embodiments,the ion-exchange resin device comprises a first column with basic ionexchange resins and a dehydrating reagent (e.g., 4 Å molecular sieves);and a second column with acidic ion exchange resins and a dehydratingreagent (e.g., 4 Å molecular sieves). In certain embodiments, theion-exchange resin device is as shown in FIG. 2.

In certain embodiments of synthesizing the C1-C19 building block ofhalichondrin A and analogs, the method further comprises the step ofdeprotecting a compound of Formula (I-b-8):

or a salt thereof,to give a compound of Formula (I-b-14):

or a salt thereof,wherein R^(1a), R^(1d), R^(4a), R^(4b), and 10 are as defined herein. Incertain embodiments, the step of deprotecting is to convert theprotecting group at R^(4c) to hydrogen. In certain embodiments, the stepof deprotecting is to convert the protecting group at R^(4c) tohydrogen, wherein both R^(4b) and R^(4c) are independently silylprotecting groups. In certain embodiments, this step of deprotecting isperformed in the presence of a source of fluoride. In certainembodiments, the step of deprotecting is performed in the presence ofHF-pyridine.

Methods for Preparing C20-C38 Building Block of Halichondrins

Provided herein are methods for preparing C20-C38 building blocks ofhalichondrins and analogs thereof (e.g., halichondrins A, B, C;homohalichondrin A, B, C; norhalichondrin A, B, C; eribulin). In certainembodiments, C20-C38 building blocks of the halichondrins are compoundsof Formula (TJ-1):

In certain embodiments, a compound of Formula (TJ-1) is a compound ofFormula (III-1). Compounds of Formula (III-1) can be prepared as shownin Scheme A.

Provided herein is a method of preparing a compound of Formula (III-1):

or a salt thereof, the method comprising a step of reducing a compoundof Formula (III-2):

or a salt thereof. The step of reducing converts the —CO₂R^(Z5a) moietyto an aldehyde moiety. In certain embodiments, the step of reducing iscarried out in the presence of a hydride (i.e., H⁻) source. Any hydridesource known in the art may be used in this transformation. Examples ofhydride sources include, but are not limited to, lithium aluminumhydride, sodium borohydride, and diisobutylaluminum hydride. In certainembodiments, the hydride source is diisobutylaluminum hydride (DIBAL).The step of reducing may optionally comprise reducing the —CO₂R^(Z5a)moiety to an alcohol, followed by oxidation of the resulting alcohol toan aldehyde to yield a compound of Formula (III-1).

As shown in Scheme A, the method of preparing a compound of Formula(III-1) optionally comprises steps of deprotecting and reprotecting themoiety corresponding to —OR^(P5). The steps of deprotection andreprotection serve to change the group R^(P5) from one protecting groupto another. For example, in certain embodiments, the group R^(P5) can bechanged from a para-methoxyphenyl (MPM) group to an acyl group viadeprotection and reprotection.

In certain embodiments, the method of preparing a C20-C38 building blockcomprises a step of deprotecting a compound of Formula (III-1), or asalt thereof, to yield a compound of Formula (III-1-a):

or a salt thereof, wherein R^(P5) of Formula (III-1) is an oxygenprotecting group. In certain embodiments, the step of deprotectingcomprises reacting a compound of Formula (III-1) in the presence of areagent for deprotection. For example, in certain embodiments, R^(P5) isa para-methoxyphenyl protecting group (MPM), and the reagent fordeprotection is an oxidant. In certain embodiments, R^(P5) is apara-methoxyphenyl protecting group (MPM), and the reagent fordeprotection is 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ). Incertain embodiments, R^(P5) is a para-methoxyphenyl protecting group(MPM), and the reagent for deprotection is an oxidant. In certainembodiments, the reagent for deprotection is dimethylboron bromide,magnesium bromide-dimethyl sulfide, ceric ammonium nitrate (CAN), or anacid. The MPM protecting group may also be removed via hydrogenolysisusing hydrogen gas.

As described herein, a compound of Formula (III-a) may be reprotected toyield a compound of Formula (III-1). Therefore, in certain embodiments,the method of preparing a C20-C38 building block comprises a step ofprotecting a compound of Formula (III-1-a), or a salt thereof, to yielda compound of Formula (III-1), or a salt thereof. In certainembodiments, the step of protecting involves acylating the free alcohol(e.g., installing R^(P5) as an acyl protecting group). In certainembodiments, the step of protecting is carried out in the presence of anacylating agent (e.g., an acyl halide or acyl anhydride). In certainembodiments, the step of protecting is carried out in the presence ofacetyl chloride or acetyl anhydride (e.g., to install R^(P5) as—C(═O)CH₃). In certain embodiments, the step of protecting is carriedout in the presence of acetyl anhydride. In certain embodiments, thestep of protecting is carried out in the presence of a coupling reagentand/or a base. In certain embodiments, the step of protecting is carriedout in the presence of an amine base (e.g., a trialkylamine such astriethylamine or N,N-diisopropylethylamine). In certain embodiments, thestep of protecting is carried out in the presence of a pyridine base orcoupling reagent. In certain embodiments, the step of coupling iscarried out in the presence of pyridine. In certain embodiments, thestep of coupling is carried out in the presence of4-dimethylaminopyridine (DMAP).

In certain embodiments, the method of preparing a C20-C38 building blockcomprises a step of protecting a compound of Formula (III-3):

or a salt thereof, to yield a compound of Formula (III-2):

or a salt thereof. The step of protecting involves protecting theprimary and secondary free alcohols of a compound of Formula (III-3) tointroduce the groups R^(Z4a) and R^(P4). The two alcohols may beprotected in separate steps or the same step, and may be protected withthe same or different protecting groups (e.g., R^(2a) and R^(P4) are thesame or different). In certain embodiments, the step of protecting iscarried out in the presence of a protecting reagent. For example, incertain embodiments, R^(Z4a) and R^(P4) are trialkylsilyl groups, andthe step of protecting is carried out in the presence of a trialkylsilylhalide or a trialkylsilyl sulfonate. For example, in certainembodiments, R^(Z4a) and R^(P4) are tert-butyldimethylsilyl (TBS), andthe step of protecting is carried out in the presence oftert-butyldimethylsilyl trifluoromethanesulfonate (“TBS-triflate” or“TBSOTf”). The step of protecting may optionally be carried out in thepresence of a base.

In certain embodiments, the method of preparing a C20-C38 building blockcomprises a step of deprotecting and cyclizing a compound of Formula(III-4):

or a salt thereof, to yield a compound of Formula (III-3):

or a salt thereof. The step of deprotecting and cyclizing involvesdeprotecting the two ketals of a compound of Formula (III-4), followedby a cyclization reaction to provide the new six-membered ring of thecompound of Formula (III-3). The deprotecting and cyclizing may be donein the same step, or in separate steps, and in either order. In certainembodiments, the step of deprotecting and cyclizing is carried out inthe presence of an acid (e.g., Lewis acid, Bronsted acid). In certainembodiments, the step of deprotecting and cyclizing is carried out inthe presence of a hydride source. In certain embodiments, the step ofdeprotecting and cyclizing is carried out in the presence of atrialkylsilyl sulfonate or trialkylsilyl halide. In certain embodiments,the step of deprotecting and cyclizing is carried out in the presence ofa trialkylsilane. In certain embodiments, the step of deprotecting andcyclizing is carried out in the presence of triethylsilyltrifluoromethylsulfonate (“TES-triflate” or “TESOTf”). In certainembodiments, the step of deprotecting and cyclizing is carried out inthe presence of triethylsilane. In certain embodiments, the step ofdeprotecting and cyclizing is carried out in the presence of TESOTf andtriethylsilane.

In certain embodiments, the method of preparing a C20-C38 building blockcomprises a step of coupling a compound of Formula (III-5):

or a salt thereof, with a compound of Formula (III-6):

or a salt thereof, in the presence of a chromium catalyst and optionallyone or more catalysts, to yield a compound of Formula (III-4):

or a salt thereof. The coupling may be any chromium-mediated couplingreaction known in the art or described herein, and involve any catalystsor reagents known in the art or described herein. In certainembodiments, the chromium catalyst is a chromium complex (i.e.,comprising a ligand). In certain embodiments, the chromium catalyst ischromium sulfonamide (see, e.g., Namba K et al., Org. Lett., 2004,6(26), 5031-5033; Ueda et al. J. Am. Chem. Soc. 2014, 136, 5171-5176).In certain embodiments, the chromium sulfonamide is of Formula (S-1),described herein. In certain embodiments, the chromium sulfonamide is ofthe following formula:

In certain embodiments, the chromium sulfonamide is formed by contactinga chromium salt (e.g., CrCl₂) with a sulfonamide. In certainembodiments, the sulfonamide is of Formula (S-2), as described herein.In certain embodiments, the sulfonamide is of the formula:

In certain embodiments, the step of coupling is carried out in thepresence of a nickel catalyst. Any nickel catalyst known in art ordescribed herein may be used. In certain embodiments, the nickelcatalyst is a catalyst of Formula (N-1), described herein. In certainembodiments, the nickel catalyst is of the following formula:

In certain embodiments, the nickel catalyst is (Me)₆Phen-NiCl₂, of theformula:

In certain embodiments, the step of coupling may be carried out in thepresence of one or more additional reagents (e.g., salts, bases,metals). In certain embodiments, the step of coupling may be carried outin the presence of one or more additional agents selected from the groupconsisting of lithium salts (e.g., LiCl), transition metals (e.g., Mn),and zirconium complexes (e.g., Cp₂ZrCl₂). In certain embodiments, thestep of coupling is be carried out in the presence of LiCl, Mn, andCp₂ZrCl₂. In certain embodiments, the step of coupling is carried out inthe presence of a proton sponge.

In certain embodiments, the method of preparing C20-C38 building blockcomprises a step of reducing a compound of Formula (III-7):

or a salt thereof, to yield a compound of Formula (III-5):

or a salt thereof. The step of reducing is to convert the —CO₂R^(Z5a)moiety to an aldehyde moiety. In certain embodiments, the step ofreducing is carried out in the presence of a hydride (i.e., H⁻) source.Any hydride source known in the art may be used in this transformation.Examples of hydride sources include, but are not limited to, lithiumaluminum hydride, sodium borohydride, and diisobutylaluminum hydride. Incertain embodiments, the hydride source is diisobutylaluminum hydride(DIBAL). The step of reducing may optionally comprise reducing the—CO₂R^(Z5a) moiety to an alcohol, followed by oxidation of the alcoholto an aldehyde to yield a compound of Formula (III-5).

C20-C38 building blocks of halichondrins (e.g., halichondrin A, B, C;homohalichondrin A, B, C; norhalichondrin A, B, C) and analogs thereofmay be of Formula (III-11):

The present invention provides methods of preparing C20-C38 buildingblocks of halichondrins, including compounds of Formula (III-11).Compounds of Formula (III-11) can be coupled with C₁-C₁₉ building blocksdescribed herein (e.g., compounds of Formula (TC-1) in order to preparethe macrocyclic right halves of the halichondrins. Compounds of Formula(III-11) may be prepared as shown in Scheme B.

In certain embodiments, the method of preparing a compound of Formula(III-11) comprises a step of protecting a compound of Formula (III-10):

or a salt thereof, to yield a compound of Formula (III-11). The step ofprotecting serves to protect the free secondary alcohol of a compound ofFormula (III-10) and install the group R^(P5). In certain embodiments,the step of protecting involves acylating the free alcohol (e.g.,installing R^(P5) as an acyl protecting group). In certain embodiments,the step of protecting is carried out in the presence of an acylatingagent (e.g., an acyl halide or acyl anhydride). In certain embodiments,the step of protecting is carried out in the presence of acetyl chlorideor acetyl anhydride (e.g., to install R^(P5) as —C(═O)CH₃). In certainembodiments, the step of protecting is carried out in the presence ofacetyl anhydride. In certain embodiments, the step of protecting iscarried out in the presence of an amine base (e.g., a trialkylamine suchas triethylamine or N,N-diisopropylethylamine). In certain embodiments,the step of protecting is carried out in the presence of a pyridine baseor coupling reagent. In certain embodiments, the step of coupling iscarried out in the presence of pyridine. In certain embodiments, thestep of protecting is carried out in the presence of a coupling reagentand/or a base. In certain embodiments, the step of coupling is carriedout in the presence of 4-dimethylaminopyridine (DMAP).

In certain embodiments, the method of preparing a C20-C38 building blockcomprises a step of reducing a compound of Formula (III-9):

or a salt thereof, to yield a compound of Formula (III-10):

or a salt thereof. The step of reducing is to convert the —CO₂R^(Z5a)moiety to an aldehyde. In certain embodiments, the step of reducing iscarried out in the presence of a hydride (i.e., H⁻) source. Any hydridesource known in the art may be used in this transformation. Examples ofhydride sources include, but are not limited to, lithium aluminumhydride, sodium borohydride, and diisobutylaluminum hydride. In certainembodiments, the hydride source is diisobutylaluminum hydride (DIBAL).The step of reducing may optionally comprise reducing the —CO₂R^(Z5a)moiety to an alcohol, followed by oxidation of the resulting alcohol toan aldehyde to yield a compound of Formula (III-10).

In certain embodiments, the method of preparing a C20-C38 building blockcomprises a step of ketalizing a compound of Formula (III-8), or a saltthereof, to yield a compound of Formula (III-9), or a salt thereof. Forexample, in certain embodiments, the method of preparing a C20-C38building block comprises a step of contacting a compound of Formula(III-8):

or a salt thereof, with a compound of the formula:

or a salt thereof, in the presence of an acid to yield a compound ofFormula (III-9):

or a salt thereof. The acid used in this transformation may be a Lewisacid or a Bronsted acid. The acid may be used in a catalytic,stoichiometric, or excess amount. In certain embodiments, the acid is aBronsted acid. In certain embodiments, the acid is a sulfonic acid. Incertain embodiments, the acid is a pyridinium salt. In certainembodiments, the acid is a pyridinium salt of a sulfonic acid. Incertain embodiments, the acid is pyridinium p-toluenesulfonate (PPTS).In certain embodiments, the step of ketalizing is carried out in thepresence of one or more additional reagents (e.g., ketals). In certainembodiments, the reaction is carried out in the presence of anadditional ketal (e.g., 2,2-dimethoxypropane). In certain embodiments,the reaction is carried out in the presence of 2,2-dimethoxypropane.

In certain embodiments, the method of preparing a C20-C38 building blockcomprises steps of deprotecting and cyclizing a compound of Formula(III-4):

or a salt thereof, to yield a compound of Formula (III-8):

or a salt thereof. The steps of deprotecting and cyclizing may becarried out in separate steps and in either order; or optionally in thesame step. In certain embodiments, the deprotecting and cyclizing arecarried out in the same step. In certain embodiments, the step ofdeprotecting and cyclizing is carried out in the presence of an acid(e.g., Lewis acid, Bronsted acid). In certain embodiments, the step ofdeprotecting and cyclizing is carried out in the presence of a hydridesource. In certain embodiments, the step of deprotecting and cyclizingis carried out in the presence of a trialkylsilyl sulfonate ortrialkylsilyl halide. In certain embodiments, the step of deprotectingand cyclizing is carried out in the presence of a trialkylsilane. Incertain embodiments, the step of deprotecting and cyclizing is carriedout in the presence of triethylsilyl trifluoromethylsulfonate(“TES-triflate” or “TESOTf”). In certain embodiments, the step ofdeprotecting and cyclizing is carried out in the presence oftriethylsilane. In certain embodiments, the step of deprotecting andcyclizing is carried out in the presence of TESOTf and triethylsilane.

Catalytic Coupling Reaction Condition

The provided coupling method between the compound of Formula (i) and thealdehyde of Formula (ii) is a catalytic chromium-mediated couplingreaction.

In certain embodiments, the provided coupling method is a catalyticasymmetric Cr-mediated coupling reaction. In certain embodiments, thechromium catalyst is a chromium complex (i.e., comprising a ligand). Incertain embodiments, the chromium catalyst is chromium sulfonamide (see,e.g., Namba K et al., Org. Lett., 2004, 6(26), 5031-5033).

In certain embodiments, the chromium sulfonamide is of Formula (S-1):

wherein

R^(s1) is halogen, —CN, —NO₂, —N₃, optionally substituted alkyl,optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted carbocyclyl, optionally substituted aryl,optionally substituted heterocyclyl, or optionally substitutedheteroaryl;

R^(s2) is hydrogen, optionally substituted alkyl, or a nitrogenprotecting group;

R^(s3) is optionally substituted alkyl, optionally substituted aryl, oroptionally substituted heteroaryl;

each instance of R^(s4) is independently hydrogen, halogen, —CN, —NO₂,—N₃, optionally substituted alkyl, optionally substituted alkenyl,optionally substituted alkynyl, optionally substituted carbocyclyl,optionally substituted aryl, optionally substituted heterocyclyl,optionally substituted heteroaryl, optionally substituted alkoxy, anoptionally substituted amino group, or optionally substituted acyl;

X¹ is halogen;

each instance of X² is independently halogen or a solvent;

u is 0 or an integer between 1 and 4, inclusive; and

g is 0, 1, 2, 3, or 4.

In certain embodiments, the chromium sulfonamide is of Formula (S-1-a)or (S-1-a′):

In certain embodiments, the chromium sulfonamide is of Formula (S-1-a):

In certain embodiments, the chromium sulfonamide is of Formula (S-1-b):

In certain embodiments, the chromium sulfonamide is of Formula (S-1-c):

In certain embodiments, the chromium sulfonamide is prepared bycontacting a chromium salt with a ligand of Formula (S-2):

wherein R^(s1), R^(s2), R^(s3), R^(s4), and u are as defined herein.

In certain embodiments, the ligand of Formula (S-2) is of Formula(S-2-a)

In certain embodiments, the ligand of Formula (S-2) is of Formula(S-2-b):

In certain embodiments, the ligand of Formula (S-2) is of Formula(S-2-b-i):

In certain embodiments, the ligand of Formula (S-2) is of Formula(S-2-c):

wherein R^(s1), R^(s2), R^(s3), R^(s4), and v are as defined herein.

In certain embodiments, the ligand of Formula (S-2) is of Formula(S-2-c-i):

In certain embodiments, the ligand of Formula (S-2) is of Formula(S-2-c-iii):

In certain embodiments, X¹ is chloride. In certain embodiments, X¹ isbromide.

In certain embodiments, X² is a halogen. In certain embodiments, X² isCl. In certain embodiments, X² is Br. In certain embodiments, X² is I.In certain embodiments, X² is a solvent. In certain embodiments, thesolvent comprises N, O, and/or S. In certain embodiments, the solventfor generating the chromium sulfonamide is THF. In certain embodiments,the solvent for generating the chromium sulfonamide is pyridine.

In certain embodiments, g is 1. In certain embodiments, g is 2. Incertain embodiments, g is 3.

In certain embodiments, u is 0. In certain embodiments, u is 1. Incertain embodiments, u is 2. In certain embodiments, u is 3.

In certain embodiments, X¹ is chloride; X² is pyridine; g is 1 or 2; andu is 1, 2, or 3. In certain embodiments, X¹ is chloride; X² is pyridine;g is 1; and u is 1, 2, or 3. In certain embodiments, X¹ is chloride; X²is pyridine; g is 2; and u is 1, 2, or 3.

In certain embodiments, R^(s1) is optionally substituted alkyl. Incertain embodiments, R^(s1) is unsubstituted alkyl. In certainembodiments, R^(s1) is methyl, ethyl, n-propyl, i-propyl, n-butyl,s-butyl, t-butyl. In certain embodiments, R¹ is i-propyl. In certainembodiments, R¹ is t-butyl. In certain embodiments, R^(s1) issubstituted alkyl.

In certain embodiments, R^(s2) is hydrogen.

In certain embodiments, R^(s3) is optionally substituted alkyl. Incertain embodiments, R^(s3) is unsubstituted alkyl. In certainembodiments, R^(s3) is methyl or ethyl. In certain embodiments, R^(s3)is substituted alkyl. In certain embodiments, R^(s3) is optionallysubstituted aryl. In certain embodiments, R^(s3) is optionallysubstituted phenyl. In certain embodiments, R^(s3) is unsubstitutedphenyl. In certain embodiments, R^(s3) is substituted phenyl. In certainembodiments, R^(s3) is halogenated phenyl. In certain embodiments,R^(s3) is optionally substituted naphthyl. In certain embodiments,R^(s3) is unsubstituted naphthyl.

In certain embodiments, each instance of R^(s4) is independentlyhydrogen, halogen, optionally substituted alkyl, optionally substitutedaryl, optionally substituted heteroaryl, or optionally substitutedalkoxy. In certain embodiments, at least one instance of R^(s4) ishydrogen. In certain embodiments, at least one instance of R^(s4) isoptionally substituted alkyl. In certain embodiments, one instance ofR^(s4) is optionally substituted alkyl. In certain embodiments, oneinstance of R^(s4) is unsubstituted alkyl (e.g., methyl or ethyl). Incertain embodiments, two instances of R^(s4) are optionally substitutedalkyl. In certain embodiments, two instances of R^(s4) are unsubstitutedalkyl (e.g., methyl or ethyl). In certain embodiments, at least onceinstance of R^(s4) is optionally substituted alkoxy. In certainembodiments, two instances of R^(s4) are optionally substituted alkoxy.In certain embodiments, two instances of R^(s4) are unsubstituted alkoxy(e.g. —OCH₃).

In certain embodiments, each instance of R^(s5) is independentlyhydrogen, halogen, optionally substituted alkyl, optionally substitutedaryl, or optionally substituted heteroaryl. In certain embodiments, atleast one instance of R^(s5) is hydrogen. In certain embodiments, atleast one instance of R^(s5) is halogen. In certain embodiments, twoinstances of R^(s5) are halogen.

In certain embodiments, v is 1. In certain embodiments, v is 2.

In certain embodiments, the ligand of Formula (S-2) is of the followingformula:

In certain embodiments, the chromium salt used to prepare the chromiumcomplex is chromium halide. In certain embodiments, the chromium salt isa chromium (II) salt. In certain embodiments, the chromium salt isCrCl₂. In certain embodiments, the chromium salt is CrBr₂. In certainembodiments, the chromium salt is a chromium (III) salt. In certainembodiments, the chromium salt is CrCl₃. In certain embodiments, thechromium salt is CrBr₃.

In certain embodiments, the amount of chromium or chromium complex iscatalytic. In certain embodiments, the chromium catalyst is at aconcentration of about 1 mol % to about 30 mol % of the compound ofFormula (i) or Formula (ii). In certain embodiments, the chromiumcatalyst is at a concentration of about 1 mol % to about 25 mol % of thecompound of Formula (i) or Formula (ii). In certain embodiments, thechromium catalyst is at a concentration of about 1 mol % to about 20 mol% of the compound of Formula (i) or Formula (ii). In certainembodiments, the chromium catalyst is at a concentration of about 1 mol% to about 15 mol % of the compound of Formula (i) or Formula (ii). Incertain embodiments, the chromium catalyst is at a concentration ofabout 5 mol % to about 15 mol % of the compound of Formula (i) orFormula (ii). In certain embodiments, the chromium catalyst is at aconcentration of about 10 mol % of the compound of Formula (i) orFormula (ii).

In certain embodiments, the provided coupling method comprises a secondcatalyst. In certain embodiments, the second catalyst is a transitionmetal or transition metal complex. In certain embodiments, the secondcatalyst is a nickel complex.

In certain embodiments, the nickel complex is of Formula (N-1):

wherein

each instance of R^(n1) and R^(n2) is independently hydrogen, halogen,—CN, —NO₂, —N₃, optionally substituted alkyl, optionally substitutedalkenyl, optionally substituted alkynyl, optionally substitutedcarbocyclyl, optionally substituted aryl, optionally substitutedheterocyclyl, optionally substituted heteroaryl, optionally substitutedalkoxy, an optionally substituted amino group, or optionally substitutedacyl;

each of R^(n3) and R^(n4) is independently halogen, —CN, —NO₂,optionally substituted alkoxy, or an optionally substituted amino group;

s is an integer between 1 and 3, inclusive; and

t is an integer between 1 and 3, inclusive.

In certain embodiments, the nickel complex of Formula (N-1) is ofFormula (N-1-a):

In certain embodiments, the nickel complex of Formula (N-1) is ofFormula (N-1-a):

In certain embodiments, the nickel complex of Formula (N-1) is ofFormula (N-1-b):

In certain embodiments, the nickel complex of Formula (N-1) is ofFormula (N-1-c):

wherein

e is 0, 1, 2, 3, 4, 5, or 6; and

f is 0, 1, 2, 3, 4, 5, or 6.

In certain embodiments, the nickel complex of Formula (N-1) is of one ofthe following formulae:

In certain embodiments, each instance of R^(n1) is independentlyhydrogen, halogen, optionally substituted alkyl, optionally substitutedaryl, optionally substituted heteroaryl, or optionally substitutedalkoxy. In certain embodiments, at least one instance of R^(n1) ishydrogen. In certain embodiments, at least one instance of R^(n1) isoptionally substituted alkyl. In certain embodiments, one instance ofR^(n1) is optionally substituted alkyl. In certain embodiments, oneinstance of R^(n1) is unsubstituted alkyl (e.g. methyl or ethyl). Incertain embodiments, two instances of R^(n1) are optionally substitutedalkyl. In certain embodiments, two instances of R^(n1) are unsubstitutedalkyl (e.g. methyl or ethyl). In certain embodiments, at least oneinstance of R^(n1) is optionally substituted. In certain embodiments,two instances of R^(n1) are optionally substituted alkoxy. In certainembodiments, two instances of R^(n1) are unsubstituted alkoxy (e.g.—OCH₃). In certain embodiments, two instances of R^(n1) are substitutedalkoxy.

In certain embodiments, each instance of R^(n2) is independentlyhydrogen, halogen, optionally substituted alkyl, optionally substitutedaryl, optionally substituted heteroaryl, or optionally substitutedalkoxy. In certain embodiments, at least one instance of R^(n2) ishydrogen. In certain embodiments, at least one instance of R^(n2) isoptionally substituted alkyl. In certain embodiments, one instance ofR^(n2) is optionally substituted alkyl. In certain embodiments, oneinstance of R^(n2) is unsubstituted alkyl (e.g. methyl or ethyl). Incertain embodiments, two instances of R^(n2) are optionally substitutedalkyl. In certain embodiments, two instances of R^(n2) are unsubstitutedalkyl (e.g. methyl or ethyl). In certain embodiments, at least oneinstance of R^(n2) is optionally substituted. In certain embodiments,two instances of R^(n2) are optionally substituted alkoxy. In certainembodiments, two instances of R^(n2) are unsubstituted alkoxy (e.g.—OCH₃). In certain embodiments, two instances of R^(n2) are substitutedalkoxy.

In certain embodiments, at least one instance of R^(n1) and R^(n2) arethe same. In certain embodiments, two instances of R^(n1) and R^(n2) arethe same.

In certain embodiments, the amount of nickel or nickel complex iscatalytic. In certain embodiments, the nickel catalyst is at aconcentration of about 0.001 mol % to about 30 mol % of the compound ofFormula (i) or Formula (ii). In certain embodiments, the nickel catalystis at a concentration of about 0.001 mol % to about 20 mol % of thecompound of Formula (i) or Formula (ii). In certain embodiments, thenickel catalyst is at a concentration of about 0.001 mol % to about 10mol % of the compound of Formula (i) or Formula (ii). In certainembodiments, the nickel catalyst is at a concentration of about 0.001mol % to about 5 mol % of the compound of Formula (i) or Formula (ii).In certain embodiments, the nickel catalyst is at a concentration ofabout 0.001 mol % to about 1 mol % of the compound of Formula (i) orFormula (ii). In certain embodiments, the nickel catalyst is at aconcentration of about 0.01 mol % to about 0.5 mol % of the compound ofFormula (i) or Formula (ii). In certain embodiments, the nickel catalystis at a concentration of about 0.05 mol % to about 0.1 mol % of thecompound of Formula (i) or Formula (ii). In certain embodiments, thenickel catalyst is at a concentration of about 0.1 mol % of the compoundof Formula (i) or Formula (ii). In certain embodiments, the nickelcatalyst is at a concentration of about 0.01 mol % to about 0.05 mol %of the compound of Formula (i) or Formula (ii). In certain embodiments,the nickel catalyst is at a concentration of about 0.05 mol % of thecompound of Formula (i) or Formula (ii).

In certain embodiments, the chromium catalyst is at a concentration ofabout 1 mol % to about 20 mol % of the compound of Formula (i) orFormula (ii) and the nickel catalyst is at a concentration of about 0.01mol % to about 0.5 mol % of the compound of Formula (i) or Formula (ii).In certain embodiments, the chromium catalyst is at a concentration ofabout 1 mol % to about 20 mol % of the compound of Formula (i) orFormula (ii) and the nickel catalyst is at a concentration of about 0.01mol % to about 0.1 mol % of the compound of Formula (i) or Formula (ii).In certain embodiments, the chromium catalyst is at a concentration ofabout 10 mol % of the compound of Formula (i) or Formula (ii) and thenickel catalyst is at a concentration of about 0.1 mol % of the compoundof Formula (i) or Formula (ii). In certain embodiments, the chromiumcatalyst is at a concentration of about 10 mol % of the compound ofFormula (i) or Formula (ii) and the nickel catalyst is at aconcentration of about 0.05 mol % of the compound of Formula (i) orFormula (ii).

In certain embodiments, an additional catalyst is present in the step ofcoupling. In certain embodiments, the additional catalyst is atransition metal or transitional metal complex. In certain embodiments,the additional catalyst is a silyl complex. In certain embodiments, theadditional catalyst is TES-Cl. In certain embodiments, the additionalcatalyst is a zirconium catalyst. In certain embodiments, the zirconiumcatalyst is a zirconium complex. In certain embodiments, the zirconiumcatalyst is Zr(Cp)₂Cl₂.

In certain embodiments, the catalysts in the step of coupling are achromium catalyst, a nickel complex, and a zirconium catalyst. Incertain embodiments, the catalysts in the step of coupling are achromium catalyst and a zirconium catalyst. In certain embodiments, thezirconium catalyst is a zirconium complex. In certain embodiments, thezirconium catalyst is Zr(Cp)₂Cl₂.

In certain embodiments, the amount of the additional catalyst isstoichiometric. In certain embodiments, the amount of zirconium complexis stoichiometric. In certain embodiments, the zirconium complex is at aconcentration of about 0.1 eq to about 5.0 eq of the compound of Formula(i) or Formula (ii). In certain embodiments, the zirconium complex is ata concentration of about 1.0 eq to about 4.0 eq of the compound ofFormula (i) or Formula (ii). In certain embodiments, the zirconiumcomplex is at a concentration of about 1.0 eq to about 3.0 eq of thecompound of Formula (i) or Formula (ii). In certain embodiments, thezirconium complex is at a concentration of about 1.0 eq to about 2.0 eqof the compound of Formula (i) or Formula (ii). In certain embodiments,the zirconium complex is at a concentration of about 1.5 eq of thecompound of Formula (i) or Formula (ii).

In certain embodiments, the step of coupling is performed in thepresence of a reducing agent. The reducing agent can reduce chromium inthe catalytic cycle. In certain embodiments, the reducing agent is atransition metal. In certain embodiments, the reducing agent ismanganese (Mn).

In certain embodiments, the reducing agent is at a concentration ofabout 1.0 eq to about 10.0 eq of the compound of Formula (i) or Formula(ii). In certain embodiments, the reducing agent is at a concentrationof about 1.0 eq to about 8.0 eq of the compound of Formula (i) orFormula (ii). In certain embodiments, the reducing agent is at aconcentration of about 1.0 eq to about 6.0 eq of the compound of Formula(i) or Formula (ii). In certain embodiments, the reducing agent is at aconcentration of about 1.0 eq to about 4.0 eq of the compound of Formula(i) or Formula (ii). In certain embodiments, the reducing agent is at aconcentration of about 4.0 eq of the compound of Formula (i) or Formula(ii).

In certain embodiments, the step of coupling is performed in thepresence of an inorganic salt. In certain embodiments, the inorganicsalt is an IA group salt. In certain embodiments, the inorganic salt isLiCl.

In certain embodiments, the inorganic salt is at a concentration ofabout 1.0 eq to about 10.0 eq of the compound of Formula (i) or Formula(ii). In certain embodiments, the inorganic salt is at a concentrationof about 1.0 eq to about 8.0 eq of the compound of Formula (i) orFormula (ii). In certain embodiments, the inorganic salt is at aconcentration of about 1.0 eq to about 6.0 eq of the compound of Formula(i) or Formula (ii). In certain embodiments, the inorganic salt is at aconcentration of about 1.0 eq to about 4.0 eq of the compound of Formula(i) or Formula (ii). In certain embodiments, the inorganic salt is at aconcentration of about 4.0 eq of the compound of Formula (i) or Formula(ii).

In certain embodiments, the provided coupling reaction can be carriedout in one or more aprotic solvents. The term “aprotic solvent” means anon-nucleophilic solvent having a boiling point range above ambienttemperature, preferably from about 25° C. to about 190° C. atatmospheric pressure. In certain embodiments, the aprotic solvent has aboiling point from about 80° C. to about 160° C. at atmosphericpressure. In certain embodiments, the aprotic solvent has a boilingpoint from about 80° C. to about 150° C. at atmospheric pressure.Examples of such solvents are CH₂Cl₂, MeCN, EtCN, toluene, DMF, diglyme,THF, and DMSO. In certain embodiments, the solvent is EtCN.

In certain embodiments, the compound of Formula (i) or Formula (ii) isat the concentration of about 0.05 to about 5.0 M. In certainembodiments, the compound of Formula (i) or Formula (ii) is at theconcentration of about 0.05 to about 3.0 M. In certain embodiments, thecompound of Formula (i) or Formula (ii) is at the concentration of about0.05 to about 1.0 M. In certain embodiments, the compound of Formula (i)or Formula (ii) is at the concentration of about 0.1 to about 1.0 M. Incertain embodiments, the compound of Formula (i) or Formula (ii) is atthe concentration of about 0.1 to about 0.5 M. In certain embodiments,the compound of Formula (i) or Formula (ii) is at the concentration ofabout 0.4 M.

Synthesis of Halichondrins

In another aspect, provided herein are methods of synthesizinghalichondrin A, B, and C, and analogs thereof (e.g., homohalichondrin A,B, C; norhalichondrin A, B, C), from the C1-C19 building blocks and theC20-C38 building blocks of halichondrins provided herein. The syntheticroutes presented herein include: (1) synthesis of the macrocyclic corevia an asymmetric nickel/chromium-mediated coupling, followed bybase-induced furan formation, and macrolactonization (Scheme T1); (2)synthesis of an unsaturated ketone intermediate vianickel/chromium-mediated coupling, followed by Dess-Martin oxidation(Schemes T2-T4); and (3) a selective acid-mediated equilibration ofC38-epi-halichondrins (Schemes T2-T4).

In Scheme T1, compounds of Formula (TJ-1) are C20-C38 building blocks,and compounds of Formula (TC-1) are C1-C19 building blocks ofhalichondrins. These building blocks can be joined via the process shownin Scheme T1 to form right halves of halichondrins (e.g., compounds ofFormula (TE-1)). Once the right half of a halichondrin is assembled, theright half can be coupled to a left halves (e.g., compounds of Formulae(TI-1), (TK-1), and (TK-1)) via the processes shown in Schemes T2-T4.

As shown in Schemes T1-T4, the C1-C19 building block of halichondrinsand analogs thereof are of Formula (TC-1). In certain embodiments, thecompound of Formula (TC-1) is of Formula (I-a-4) or a salt thereof. Incertain embodiments, the compound of Formula (TC-1) is of Formula(I-b-6) or a salt thereof. In certain embodiments, the compound ofFormula (TC-1) is of Formula (I-b-9) or a salt thereof. In certainembodiments, the compound of Formula (TC-1) is of Formula (I-b-13) or asalt thereof.

In certain embodiments, as shown in Scheme T2, the halichondrins andanalogs synthesized from the C1-C19 building blocks and C20-C38 buildingblocks are of Formula (TI). In certain embodiments, the compound ofFormula (TI) is of the formula:

In certain embodiments, the compound of Formula (TI) is of the formula:

In certain embodiments, the compound of Formula (TI) is of the formula:

In certain embodiments, preparation of compounds of Formula (TI) andsalts thereof comprises cyclizing an intermediate compound of Formula(TF-1) or a salt thereof (see Scheme T2). In certain embodiments, when acompound of Formula (TF-1) is protected (e.g., with silyl or benzylicprotecting groups), the synthetic route comprises a deprotection stepprior to cyclization. In certain embodiments, deprotection of a compoundof Formula (TF-1) comprises a source of fluoride (e.g., TBAF,HF.pyridine). In certain embodiments, deprotection of a compound ofFormula (TF-1) comprises a hydrogenolysis (e.g., a palladium or nickelcatalyst and H₂) or oxidation (e.g., DDQ) step. In certain embodiments,the cyclization conditions comprise an acid. In certain embodiments, thecyclization conditions comprise a Brønsted acid (i.e., a source of H⁺).In certain embodiments, the cyclization conditions comprise an organicacid (e.g., PPTS). In certain embodiments, the cyclization conditionsprovide a compound of Formula (TI) as a single diastereomer. In certainembodiments, the cyclization conditions provide a diastereomeric mixturethat is enriched in one of two epimeric C38 ketals. In certainembodiments, the synthetic route comprises an equilibration step toenrich a compound of Formula (TI) in one of two epimeric C38 ketals. Incertain embodiments, the equilibration step enriches a compound ofFormula (TI) in the (R)-epimer. In certain embodiments, theequilibration step enriches a compound of Formula (TI) in the (R)-epimerin a range of 2:1, 3:1, 4:1, 5:1, or >5:1. In certain embodiments, theequilibration step enriches a compound of Formula (TI) in the(S)-epimer. In certain embodiments, the equilibration step enriches acompound of Formula (TI) in the (S)-epimer in a range of 2:1, 3:1, 4:1,5:1, 10:1, or >10:1. In certain embodiments, the equilibration stepcomprises a Lewis acid. In certain embodiments, the equilibration stepcomprises a silyl Lewis acid (e.g., a silicon tetrahalide or andorganosilicon halide or triflate). In certain embodiments, theequilibration step comprises trimethylsilyl triflate. In certainembodiments, the equilibration step comprises a solvent. In certainembodiments, the equilibration step comprises a halogenated (e.g.,dichloromethane) or ethereal (e.g., diethylether) solvent.

As described herein, the deprotection, cyclization, and equilibration ofa compound of Formula (TF-1) to yield a compound of Formula (TI) can beperformed in two steps when particular protecting groups are utilized onthe intermediate (TF-1). For example, when R^(P1), R^(P2), and R^(P8)are TBS, and R^(P3), R^(P7), and R^(P4) are TES, the deprotection,cyclization, and equilibration can be performed in two steps by treatinga compound of Formula (TF-1) with a fluoride source, followed by anacid. Any fluoride source known in the art may be used. Examples offluoride sources include, but are not limited to, HF-pyridine, KF, CsF,AgF, ammonium fluoride, and tetraalkylammonium fluorides. In certainembodiments, the fluoride source is a tetraalkylammonium fluoride (e.g.,tetramethylammonium fluoride, tetraethylammonium fluoride,tetrabutylammonium fluoride, benzyltrimethylammonium fluoride). Incertain embodiments, the acid is a Bronsted acid. In certainembodiments, the acid is an inorganic acid (e.g., HCl, HF, HBr). Incertain embodiments, the acid is an organic acid (e.g., carboxylic acid,sulfinic acid, sulfonic acid, phosphoric acid). In certain embodiments,the acid is a carboxylic acid (e.g., acetic acid, trifluoroacetic acid(TFA), pivalic acid). For example, in certain embodiments whereinR^(P1), R^(P2), and R^(P8) are TBS, and R^(P3), R^(P7), and R^(P4) areTES, a compound of Formula (TF-1) can be converted to a compound ofFormula (TI) by treatment with TBAF and pivalic acid, followed bytreatment with PPTS (see, e.g., FIG. 29).

In certain embodiments, preparation of C38 epi-halichondrin A comprisesan acid-mediated equilibration of the C38 ketal stereocenter ofhalichondrin A. In certain embodiments, preparation of halichondrin Acomprises an acid-mediated equilibration of the C38 ketal stereocenterof C38 epi-halichondrin A.

In certain embodiments, preparation of C38 epi-halichondrin B comprisesan acid-mediated equilibration of the C38 ketal stereocenter ofhalichondrin B. In certain embodiments, preparation of halichondrin Bcomprises an acid-mediated equilibration of the C38 ketal stereocenterof C38 epi-halichondrin B.

In certain embodiments, preparation of C38 epi-halichondrin C comprisesan acid-mediated equilibration of the C38 ketal stereocenter ofhalichondrin C. In certain embodiments, preparation of halichondrin Ccomprises an acid-mediated equilibration of the C38 ketal stereocenterof C38 epi-halichondrin C.

In certain embodiments, as shown in Scheme T3, the halichondrins andanalogs synthesized from the C1-C19 building blocks and C20-C38 buildingblocks are of Formula (TII). In certain embodiments, the compound ofFormula (TII) is of one of the following formulae:

In certain embodiments, preparation of compounds of Formula (TII) andsalts thereof comprises cyclizing an intermediate compound of Formula(TG-1) or a salt thereof (see Scheme T3). In certain embodiments, when acompound of Formula (TG-1) is protected (e.g., with silyl or benzylicprotecting groups), the synthetic route comprises a deprotection stepprior to cyclization. In certain embodiments, deprotection of a compoundof Formula (TG-1) comprises a source of fluoride (e.g., TBAF,HF.pyridine). In certain embodiments, deprotection of a compound ofFormula (TG-1) comprises a hydrogenolysis (e.g., a palladium or nickelcatalyst and H₂) or oxidation (e.g., DDQ) step. In certain embodiments,the cyclization conditions comprise an acid. In certain embodiments, thecyclization conditions comprise a Brønsted acid (i.e., a source of H+).In certain embodiments, the cyclization conditions comprise an organicacid (e.g., PPTS). In certain embodiments, the cyclization conditionsprovide a compound of Formula (TII) as a single diastereomer. In certainembodiments, the cyclization conditions provide a diastereomeric mixturethat is enriched in one of two epimeric C38 ketals. In certainembodiments, the synthetic route comprises an equilibration step toenrich a compound of Formula (TII) in one of two epimeric C38 ketals. Incertain embodiments, the equilibration step enriches a compound ofFormula (TII) in the (R)-epimer. In certain embodiments, theequilibration step enriches a aldehyde of Formula (ii) in the (R)-epimerin a range of 2:1, 3:1, 4:1, 5:1, or >5:1. In certain embodiments, theequilibration step enriches a aldehyde of Formula (ii) in the(S)-epimer. In certain embodiments, the equilibration step enriches aaldehyde of Formula (ii) in the (S)-epimer in a range of 2:1, 3:1, 4:1,5:1, 10:1, or >10:1. In certain embodiments, the equilibration stepcomprises a Lewis acid. In certain embodiments, the equilibration stepcomprises a silyl Lewis acid (e.g., a silicon tetrahalide or andorganosilicon halide or triflate). In certain embodiments, theequilibration step comprises trimethylsilyl triflate. In certainembodiments, the equilibration step comprises a solvent. In certainembodiments, the equilibration step comprises a halogenated (e.g.,dichloromethane) or ethereal (e.g., diethylether) solvent. In certainembodiments, when R^(T7) is not hydrogen, the synthetic route comprisesa hydrolysis step comprising a base (e.g., lithium, sodium, or potassiumhydroxide).

As described herein, the deprotection, cyclization, and equilibration ofa compound of Formula (TG-1) to yield a compound of Formula (TII) can beperformed in two synthetic steps when particular protecting groups areutilized for the intermediate (TG-1). For example, when R^(P10) is TBS,and R^(P8) and R^(P9) are TES, the deprotection, cyclization, andequilibration can be performed in two steps by treating a compound ofFormula (TG-1) with a fluoride source, followed by an acid. Any fluoridesource known in the art may be used. Examples of fluoride sourcesinclude, but are not limited to, HF-pyridine, KF, CsF, AgF, ammoniumfluoride, and tetraalkylammonium fluorides. In certain embodiments, thefluoride source is a tetraalkylammonium fluoride (e.g.,tetramethylammonium fluoride, tetraethylammonium fluoride,tetrabutylammonium fluoride, benzyltrimethylammonium fluoride). Incertain embodiments, the acid is a Bronsted acid. In certainembodiments, the acid is an inorganic acid (e.g., HCl, HF, HBr). Incertain embodiments, the acid is an organic acid (e.g., carboxylic acid,sulfinic acid, sulfonic acid, phosphoric acid). In certain embodiments,the acid is a carboxylic acid (e.g., acetic acid, trifluoroacetic acid(TFA), pivalic acid). For example, in certain embodiments whereinR^(P10) is TBS, and R^(P8) and R^(P9) are TES, a compound of Formula(TG-1) can be converted to a compound of Formula (TII) by treatment withTBAF and pivalic acid, followed by treatment with PPTS (see, e.g., FIG.29).

In certain embodiments, preparation of a compound of Formula (TG-1) orsalt thereof comprises joining an intermediate compound of Formula(TE-1) or salt thereof and an intermediate of Formula (TK-1) or saltthereof (see Scheme T3). In certain embodiments, when R^(TZ4) is—CH₂OR^(TZ4a) and R^(TZ4a) is a protecting group, the synthetic routecomprises a deprotection step. In certain embodiments, when R^(TZ4a) isa silyl protecting group (e.g., t-butyldimethylsilyl), selectivedeprotection of R^(TZ4a) comprises a mild source of fluoride (e.g.,TBAF, HF.pyridine). In certain embodiments, when R^(TZ4a) is —CH₂OH, thesynthetic route comprises an oxidation step. In certain embodiments,R^(TZ4) is oxidized into an aldehyde (—CHO) under mild and selectiveconditions (e.g., Dess-Martin periodinane, SO₃.pyridine, or Swernoxidation). Compounds of Formula (TE-1) are joined with a compound ofFormula (TK-1) under reductive coupling conditions. In certainembodiments, the conditions used to join a compound of Formula (TE-1)with a compound of Formula (TK-1) comprise a transition metal (e.g.,nickel or chromium). In certain embodiments, the coupling reaction iscatalytic in transition metal (e.g., 2-40 mol %). In certainembodiments, the coupling reaction is stoichiometric in transition metal(e.g., 1-3 equivalents). In certain embodiments, the coupling comprisesa ligand or ligated transition metal complex. The reaction used to joina compound of Formula (TE-1) and Formula (TK-1) provides an intermediatehydroxy group that must be oxidized to provide a compound of Formula(TG-1). In certain embodiments, the oxidation is carried out under mildand selective conditions (e.g., Dess-Martin periodinane, SO₃.pyridine,or Swern oxidation).

In certain embodiments, as shown in Scheme T4, the halichondrins andanalogs synthesized from the C1-C19 building blocks and C20-C38 buildingblocks are of Formula (TIII). In certain embodiments, the compound ofFormula (TIII) is of one of the following formulae:

In certain embodiments, preparation of compounds of Formula (TIII) andsalts thereof comprises cyclizing an intermediate compound of Formula(TH-1) or a salt thereof (see Scheme T4). In certain embodiments, when acompound of Formula (TH-1) is protected (e.g., with silyl or benzylicprotecting groups), the synthetic route comprises a deprotection stepprior to cyclization. In certain embodiments, deprotection of a compoundof Formula (TG-1) comprises a source of fluoride (e.g., TBAF,HF.pyridine). In certain embodiments, deprotection of a compound ofFormula (TH-1) comprises a hydrogenolysis (e.g., a palladium or nickelcatalyst and H₂) or oxidation (e.g., DDQ) step. In certain embodiments,the cyclization conditions comprise an acid. In certain embodiments, thecyclization conditions comprise a Brønsted acid (i.e., a source of H+).In certain embodiments, the cyclization conditions comprise an organicacid (e.g., PPTS). In certain embodiments, the cyclization conditionsprovide a compound of Formula (TIII) as a single diastereomer. Incertain embodiments, the cyclization conditions provide a diastereomericmixture that is enriched in one of two epimeric C38 ketals. In certainembodiments, the synthetic route comprises an equilibration step toenrich a compound of Formula (TIII) in one of two epimeric C38 ketals.In certain embodiments, the equilibration step enriches a compound ofFormula (TIII) in the (R)-epimer. In certain embodiments, theequilibration step enriches a compound of Formula (TIII) in the(R)-epimer in a range of 2:1, 3:1, 4:1, 5:1, or >5:1. In certainembodiments, the equilibration step enriches a compound of Formula(TIII) in the (S)-epimer. In certain embodiments, the equilibration stepenriches a compound of Formula (TIII) in the (S)-epimer in a range of2:1, 3:1, 4:1, 5:1, 10:1, or >10:1. In certain embodiments, theequilibration step comprises a Lewis acid. In certain embodiments, theequilibration step comprises a silyl Lewis acid (e.g., a silicontetrahalide or and organosilicon halide or triflate). In certainembodiments, the equilibration step comprises trimethylsilyl triflate.In certain embodiments, the equilibration step comprises a solvent. Incertain embodiments, the equilibration step comprises a halogenated(e.g., dichloromethane) or ethereal (e.g., diethylether) solvent.

In certain embodiments, preparation of a compound of Formula (TH-1) or asalt thereof comprises joining an intermediate compound of Formula(TE-1) or a salt thereof and an intermediate of Formula (TL-1) or a saltthereof. In certain embodiments, when R^(TZ4) is —CH₂OR^(TZ4a) andR^(TZ4a) is a protecting group, the synthetic route comprises adeprotection step. In certain embodiments, when R^(TZ4a) is a silylprotecting group (e.g., t-butyldimethylsilyl), selective deprotection ofR^(TZ4a) comprises a mild source of fluoride (e.g., TBAF, HF.pyridine).In certain embodiments, when R^(TZ4) is —CH₂OH, the synthetic routecomprises an oxidation step. In certain embodiments, R^(TZ4) is oxidizedinto an aldehyde (—CHO) under mild and selective conditions (e.g.,Dess-Martin periodinane, SO₃.pyridine, or Swern oxidation). Compounds ofFormula (TE-1) are joined with a compound of Formula (TL-1) underreductive coupling conditions. In certain embodiments, the conditionsused to join a compound of Formula (TE-1) with a compound of Formula(TL-1) comprise a transition metal (e.g., nickel or chromium). Incertain embodiments, the coupling reaction is catalytic in transitionmetal (e.g., 2-40 mol %). In certain embodiments, the coupling reactionis stoichiometric in transition metal (e.g., 1-3 equivalents). Incertain embodiments, the coupling comprises a ligand or ligatedtransition metal complex. The reaction used to join a compound ofFormula (TE-1) and Formula (TL-1) provides an intermediate hydroxy groupthat must be oxidized to provide a compound of Formula (TH-1). Incertain embodiments, the oxidation is carried out under mild andselective conditions (e.g., Dess-Martin periodinane, SO₃.pyridine, orSwern oxidation).

Groups R^(P1-P19)

As generally described herein, R^(P1), R^(P2), R^(P3), R^(P4), R^(P5),R^(P6), R^(P7), R^(P8), R^(P9), R^(P10), R^(P11), R^(P12), R^(P13),R^(P14), R^(P15), R^(P16), R^(P17), R^(P18), and R^(P19) are eachindependently hydrogen, substituted or unsubstituted alkyl, optionallysubstituted acyl, or an oxygen protecting group.

In certain embodiments, R^(P1) is hydrogen. In certain embodiments,R^(P1) is substituted or unsubstitituted alkyl. In certain embodiments,R^(P1) is substituted or unsubstituted C₁₋₆ alkyl. In certainembodiments, R^(P1) is substituted or unsubstituted, branched C₁₋₆alkyl. In certain embodiments, R^(P1) is unsubstituted C₁₋₆ alkyl. Incertain embodiments, R^(P1) is methyl. In certain embodiments, R^(P1) isethyl. In certain embodiments, R^(P1) is propyl. In certain embodiments,R^(P1) is iso-propyl. In certain embodiments, R^(P1) is t-butyl. Incertain embodiments, R^(P1) is an oxygen protecting group. In certainembodiments, R^(P1) is a silyl protecting group. In certain embodiments,R^(P1) is a trialkyl silyl protecting group. In certain embodiments,R^(P1) is a t-butyldimethylsilyl protecting group. In certainembodiments, R^(P1) is a trimethylsilyl protecting group. In certainembodiments, R^(P1) is a triethylsilyl protecting group. In certainembodiments, R^(P1) is a t-butyldiphenylsilyl protecting group. Incertain embodiments, R^(P1) is a triisopropylsilyl protecting group. Incertain embodiments, R^(P1) is a benzylic protecting group. In certainembodiments, R^(P1) is a p-methoxybenzyl protecting group. In certainembodiments, R^(P1) is an acyl protecting group. In certain embodiments,R^(P1) is an acetyl protecting group. In certain embodiments, R^(P1) isa benzoyl protecting group. In certain embodiments, R^(P1) is a p-nitrobenzoyl protecting group. In certain embodiments, R^(P1) is a pivaloylprotecting group. In certain embodiments, R^(P1) is a t-butyl carbonate(BOC) protecting group. In certain embodiments, R^(P1) is an acetalprotecting group. In certain embodiments, R^(P1) is a tetrahydropyranylprotecting group. In certain embodiments, R^(P1) is an alkoxyalkylprotecting group. In certain embodiments, R^(P1) is an ethoxyethylprotecting group.

In certain embodiments, R^(P2) is hydrogen. In certain embodiments,R^(P2) is substituted or unsubstitituted alkyl. In certain embodiments,R^(P2) is substituted or unsubstituted C₁₋₆ alkyl. In certainembodiments, R^(P2) is substituted or unsubstituted, branched C₁₋₆alkyl. In certain embodiments, R^(P2) is unsubstituted C₁₋₆ alkyl. Incertain embodiments, R^(P2) is methyl. In certain embodiments, R^(P2) isethyl. In certain embodiments, R^(P2) is propyl. In certain embodiments,R^(P2) is iso-propyl. In certain embodiments, R^(P2) is t-butyl. Incertain embodiments, R^(P2) is an oxygen protecting group. In certainembodiments, R^(P2) is a silyl protecting group. In certain embodiments,R^(P2) is a trialkyl silyl protecting group. In certain embodiments,R^(P2) is a t-butyldimethylsilyl protecting group. In certainembodiments, R^(P2) is a trimethylsilyl protecting group. In certainembodiments, R^(P2) is a triethylsilyl protecting group. In certainembodiments, R^(P2) is a t-butyldiphenylsilyl protecting group. Incertain embodiments, R^(P2) is a triisopropylsilyl protecting group. Incertain embodiments, R^(P2) is a benzylic protecting group. In certainembodiments, R^(P2) is a p-methoxybenzyl protecting group. In certainembodiments, R^(P2) is an acyl protecting group. In certain embodiments,R^(P2) is an acetyl protecting group. In certain embodiments, R^(P2) isa benzoyl protecting group. In certain embodiments, R^(P2) is a p-nitrobenzoyl protecting group. In certain embodiments, R^(Y)2 is a pivaloylprotecting group. In certain embodiments, R^(P2) is a t-butyl carbonate(BOC) protecting group. In certain embodiments, R^(P2) is an acetalprotecting group. In certain embodiments, R^(P2) is a tetrahydropyranylprotecting group. In certain embodiments, R^(P2) is an alkoxyalkylprotecting group. In certain embodiments, R^(P2) is an ethoxyethylprotecting group.

In certain embodiments, R^(P3) is hydrogen. In certain embodiments,R^(P3) is substituted or unsubstitituted alkyl. In certain embodiments,R^(P3) is substituted or unsubstituted C₁₋₆ alkyl. In certainembodiments, R^(P3) is substituted or unsubstituted, branched C₁₋₆alkyl. In certain embodiments, R^(P3) is unsubstituted C₁₋₆ alkyl. Incertain embodiments, R^(P3) is methyl. In certain embodiments, R^(P3) isethyl. In certain embodiments, R^(P3) is propyl. In certain embodiments,R^(P3) is iso-propyl. In certain embodiments, R^(P3) is t-butyl. Incertain embodiments, R^(P3) is an oxygen protecting group. In certainembodiments, R^(P3) is a silyl protecting group. In certain embodiments,R^(P3) is a trialkyl silyl protecting group. In certain embodiments,R^(P3) is a t-butyldimethylsilyl protecting group. In certainembodiments, R^(P3) is a trimethylsilyl protecting group. In certainembodiments, R^(P3) is a triethylsilyl protecting group. In certainembodiments, R^(P3) is a t-butyldiphenylsilyl protecting group. Incertain embodiments, R^(P3) is a triisopropylsilyl protecting group. Incertain embodiments, R^(P3) is a benzylic protecting group. In certainembodiments, R^(Y3) is a p-methoxybenzyl protecting group. In certainembodiments, R^(Y3) is an acyl protecting group. In certain embodiments,R^(P3) is an acetyl protecting group. In certain embodiments, R^(P3) isa benzoyl protecting group. In certain embodiments, R^(P3) is a p-nitrobenzoyl protecting group. In certain embodiments, R^(P3) is a pivaloylprotecting group. In certain embodiments, R^(P3) is a t-butyl carbonate(BOC) protecting group. In certain embodiments, R^(P3) is an acetalprotecting group. In certain embodiments, R^(P3) is a tetrahydropyranylprotecting group. In certain embodiments, R^(P3) is an alkoxyalkylprotecting group. In certain embodiments, R^(P3) is an ethoxyethylprotecting group.

In certain embodiments, R^(P4) is hydrogen. In certain embodiments,R^(P4) is substituted or unsubstitituted alkyl. In certain embodiments,R^(P4) is substituted or unsubstituted C₁₋₆ alkyl. In certainembodiments, R^(P4) is substituted or unsubstituted, branched C₁₋₆alkyl. In certain embodiments, R^(P4) is unsubstituted C₁₋₆ alkyl. Incertain embodiments, R^(P4) is methyl. In certain embodiments, R^(P4) isethyl. In certain embodiments, R^(P4) is propyl. In certain embodiments,R^(P4) is iso-propyl. In certain embodiments, R^(P4) is t-butyl. Incertain embodiments, R^(P4) is an oxygen protecting group. In certainembodiments, R^(P4) is a silyl protecting group. In certain embodiments,R^(P4) is a trialkyl silyl protecting group. In certain embodiments,R^(P4) is a t-butyldimethylsilyl protecting group. In certainembodiments, R^(P4) is a trimethylsilyl protecting group. In certainembodiments, R^(P4) is a triethylsilyl protecting group. In certainembodiments, R^(P4) is a t-butyldiphenylsilyl protecting group. Incertain embodiments, R^(P4) is a triisopropylsilyl protecting group. Incertain embodiments, R^(P4) is a benzylic protecting group. In certainembodiments, R^(P4) is a p-methoxybenzyl protecting group. In certainembodiments, R^(P4) is an acyl protecting group. In certain embodiments,R^(P4) is an acetyl protecting group. In certain embodiments, R^(P4) isa benzoyl protecting group. In certain embodiments, R^(P4) is a p-nitrobenzoyl protecting group. In certain embodiments, R^(P4) is a pivaloylprotecting group. In certain embodiments, R^(P4) is a t-butyl carbonate(BOC) protecting group. In certain embodiments, R^(P4) is an acetalprotecting group. In certain embodiments, R^(P4) is a tetrahydropyranylprotecting group. In certain embodiments, R^(P4) is an alkoxyalkylprotecting group. In certain embodiments, R^(P4) is an ethoxyethylprotecting group.

In certain embodiments, R^(P5) is hydrogen. In certain embodiments,R^(P5) is substituted or unsubstitituted alkyl. In certain embodiments,R^(P5) is substituted or unsubstituted C₁₋₆ alkyl. In certainembodiments, R^(P5) is substituted or unsubstituted, branched C₁₋₆alkyl. In certain embodiments, R^(P5) is unsubstituted C₁₋₆ alkyl. Incertain embodiments, R^(P5) is methyl. In certain embodiments, R^(P5) isethyl. In certain embodiments, R^(P5) is propyl. In certain embodiments,R^(P5) is iso-propyl. In certain embodiments, R^(P5) is t-butyl. Incertain embodiments, R^(P5) is an oxygen protecting group. In certainembodiments, R^(P5) is a silyl protecting group. In certain embodiments,R^(P5) is a trialkyl silyl protecting group. In certain embodiments,R^(P5) is a t-butyldimethylsilyl protecting group. In certainembodiments, R^(P5) is a trimethylsilyl protecting group. In certainembodiments, R^(P5) is a triethylsilyl protecting group. In certainembodiments, R^(P5) is a t-butyldiphenylsilyl protecting group. Incertain embodiments, R^(P5) is a triisopropylsilyl protecting group. Incertain embodiments, R^(P5) is a benzylic protecting group. In certainembodiments, R^(P5) is a p-methoxybenzyl protecting group. In certainembodiments, R^(P5) is optionally substituted acyl. In certainembodiments, R^(P5) is unsubstituted acyl. In certain embodiments,R^(P5) is an acyl protecting group. In certain embodiments, R^(P5) is anacetyl protecting group. In certain embodiments, R^(P5) is a benzoylprotecting group. In certain embodiments, R^(P5) is a p-nitro benzoylprotecting group. In certain embodiments, R^(P5) is a pivaloylprotecting group. In certain embodiments, R^(P5) is a t-butyl carbonate(BOC) protecting group. In certain embodiments, R^(P5) is an acetalprotecting group. In certain embodiments, R^(Y5) is a tetrahydropyranylprotecting group. In certain embodiments, R^(P5) is an alkoxyalkylprotecting group. In certain embodiments, R^(P5) is an ethoxyethylprotecting group.

In certain embodiments, R^(P6) is hydrogen. In certain embodiments,R^(P6) is substituted or unsubstitituted alkyl. In certain embodiments,R^(P6) is substituted or unsubstituted C₁₋₆ alkyl. In certainembodiments, R^(P6) is substituted or unsubstituted, branched C₁₋₆alkyl. In certain embodiments, R^(P6) is unsubstituted C₁₋₆ alkyl. Incertain embodiments, R^(P6) is methyl. In certain embodiments, R^(P6) isethyl. In certain embodiments, R^(P6) is propyl. In certain embodiments,R^(P6) is iso-propyl. In certain embodiments, R^(P6) is t-butyl. Incertain embodiments, R^(P6) is an oxygen protecting group. In certainembodiments, R^(P6) is a silyl protecting group. In certain embodiments,R^(P6) is a trialkyl silyl protecting group. In certain embodiments,R^(P6) is a t-butyldimethylsilyl protecting group. In certainembodiments, R^(P6) is a trimethylsilyl protecting group. In certainembodiments, R^(P6) is a triethylsilyl protecting group. In certainembodiments, R^(P6) is a t-butyldiphenylsilyl protecting group. Incertain embodiments, R^(P6) is a triisopropylsilyl protecting group. Incertain embodiments, R^(P6) is a benzylic protecting group. In certainembodiments, R^(P6) is a p-methoxybenzyl protecting group. In certainembodiments, R^(P6) is an acyl protecting group. In certain embodiments,R^(P6) is an acetyl protecting group. In certain embodiments, R^(P6) isa benzoyl protecting group. In certain embodiments, R^(P6) is a p-nitrobenzoyl protecting group. In certain embodiments, R^(P6) is a pivaloylprotecting group. In certain embodiments, R^(P6) is a t-butyl carbonate(BOC) protecting group. In certain embodiments, R^(P6) is an acetalprotecting group. In certain embodiments, R^(P6) is a tetrahydropyranylprotecting group. In certain embodiments, R^(P6) is an alkoxyalkylprotecting group. In certain embodiments, R^(P6) is an ethoxyethylprotecting group.

In certain embodiments, R^(P7) is hydrogen. In certain embodiments,R^(P7) is substituted or unsubstitituted alkyl. In certain embodiments,R^(P7) is substituted or unsubstituted C₁₋₆ alkyl. In certainembodiments, R^(P7) is substituted or unsubstituted, branched C₁₋₆alkyl. In certain embodiments, R^(P7) is unsubstituted C₁₋₆ alkyl. Incertain embodiments, R^(P7) is methyl. In certain embodiments, R^(p7) isethyl. In certain embodiments, R^(P7) is propyl. In certain embodiments,R^(P7) is iso-propyl. In certain embodiments, R^(P7) is t-butyl. Incertain embodiments, R^(P7) is an oxygen protecting group. In certainembodiments, R^(p7) is a silyl protecting group. In certain embodiments,R^(P7) is a trialkyl silyl protecting group. In certain embodiments,R^(P7) is a t-butyldimethylsilyl protecting group. In certainembodiments, R^(P7) is a trimethylsilyl protecting group. In certainembodiments, R^(P7) is a triethylsilyl protecting group. In certainembodiments, R^(P7) is a t-butyldiphenylsilyl protecting group. Incertain embodiments, R^(P7) is a triisopropylsilyl protecting group. Incertain embodiments, R^(P7) is a benzylic protecting group. In certainembodiments, R^(P7) is a p-methoxybenzyl protecting group. In certainembodiments, R^(P7) is an acyl protecting group. In certain embodiments,R^(P7) is an acetyl protecting group. In certain embodiments, R^(P7) isa benzoyl protecting group. In certain embodiments, R^(P7) is a p-nitrobenzoyl protecting group. In certain embodiments, R^(P7) is a pivaloylprotecting group. In certain embodiments, R^(P7) is a t-butyl carbonate(BOC) protecting group. In certain embodiments, R^(P7) is an acetalprotecting group. In certain embodiments, R^(P7) is a tetrahydropyranylprotecting group. In certain embodiments, R^(P7) is an alkoxyalkylprotecting group. In certain embodiments, R^(P7) is an ethoxyethylprotecting group.

In certain embodiments, R^(P8) is hydrogen. In certain embodiments,R^(P8) is substituted or unsubstitituted alkyl. In certain embodiments,R^(P8) is substituted or unsubstituted C₁₋₆ alkyl. In certainembodiments, R^(P8) is substituted or unsubstituted, branched C₁₋₆alkyl. In certain embodiments, R^(P8) is unsubstituted C₁₋₆ alkyl. Incertain embodiments, R^(P8) is methyl. In certain embodiments, R^(P8) isethyl. In certain embodiments, R^(P8) is propyl. In certain embodiments,R^(P8) is iso-propyl. In certain embodiments, R^(P8) is t-butyl. Incertain embodiments, R^(P8) is an oxygen protecting group. In certainembodiments, R^(P8) is a silyl protecting group. In certain embodiments,R^(P8) is a trialkyl silyl protecting group. In certain embodiments,R^(P8) is a t-butyldimethylsilyl protecting group. In certainembodiments, R^(P8) is a trimethylsilyl protecting group. In certainembodiments, R^(P8) is a triethylsilyl protecting group. In certainembodiments, R^(P8) is a t-butyldiphenylsilyl protecting group. Incertain embodiments, R^(P8) is a triisopropylsilyl protecting group. Incertain embodiments, R^(P8) is a benzylic protecting group. In certainembodiments, R^(P8) is a p-methoxybenzyl protecting group. In certainembodiments, R^(P8) is an acyl protecting group. In certain embodiments,R^(P8) is an acetyl protecting group. In certain embodiments, R^(P8) isa benzoyl protecting group. In certain embodiments, R^(P8) is a p-nitrobenzoyl protecting group. In certain embodiments, R^(P8) is a pivaloylprotecting group. In certain embodiments, R^(P8) is a t-butyl carbonate(BOC) protecting group. In certain embodiments, R^(P8) is an acetalprotecting group. In certain embodiments, R^(P8) is a tetrahydropyranylprotecting group. In certain embodiments, R^(P8) is an alkoxyalkylprotecting group. In certain embodiments, R^(P8) is an ethoxyethylprotecting group.

In certain embodiments, R^(P9) is hydrogen. In certain embodiments,R^(P9) is substituted or unsubstitituted alkyl. In certain embodiments,R^(P9) is substituted or unsubstituted C₁₋₆ alkyl. In certainembodiments, R^(P9) is substituted or unsubstituted, branched C₁₋₆alkyl. In certain embodiments, R^(P9) is unsubstituted C₁₋₆ alkyl. Incertain embodiments, R^(P9) is methyl. In certain embodiments, R^(P) isethyl. In certain embodiments, R^(P9) is propyl. In certain embodiments,R^(P9) is iso-propyl. In certain embodiments, R^(P9) is t-butyl. Incertain embodiments, R^(P9) is an oxygen protecting group. In certainembodiments, R^(P9) is a silyl protecting group. In certain embodiments,R^(P9) is a trialkyl silyl protecting group. In certain embodiments,R^(P9) is a t-butyldimethylsilyl protecting group. In certainembodiments, R^(P9) is a trimethylsilyl protecting group. In certainembodiments, R^(P9) is a triethylsilyl protecting group. In certainembodiments, R^(P9) is a t-butyldiphenylsilyl protecting group. Incertain embodiments, R^(P9) is a triisopropylsilyl protecting group. Incertain embodiments, R^(P9) is a benzylic protecting group. In certainembodiments, R^(P9) is a p-methoxybenzyl protecting group. In certainembodiments, R^(P9) is an acyl protecting group. In certain embodiments,R^(P9) is an acetyl protecting group. In certain embodiments, R^(P9) isa benzoyl protecting group. In certain embodiments, R^(P9) is a p-nitrobenzoyl protecting group. In certain embodiments, R^(P9) is a pivaloylprotecting group. In certain embodiments, R^(P9) is a t-butyl carbonate(BOC) protecting group. In certain embodiments, R^(P9) is an acetalprotecting group. In certain embodiments, R^(P9) is a tetrahydropyranylprotecting group. In certain embodiments, R^(P9) is an alkoxyalkylprotecting group. In certain embodiments, R^(P9) is an ethoxyethylprotecting group.

In certain embodiments, R^(P10) is hydrogen. In certain embodiments,R^(P10) is substituted or unsubstitituted alkyl. In certain embodiments,R^(P10) is substituted or unsubstituted C₁₋₆ alkyl. In certainembodiments, R^(P10) is substituted or unsubstituted, branched C₁₋₆alkyl. In certain embodiments, R^(P10) is unsubstituted C₁₋₆ alkyl. Incertain embodiments, R^(P10) is methyl. In certain embodiments, R^(P10)is ethyl. In certain embodiments, R^(P10) is propyl. In certainembodiments, R^(P10) is iso-propyl. In certain embodiments, R^(P10) ist-butyl. In certain embodiments, R^(P10) is an oxygen protecting group.In certain embodiments, R^(P10) is a silyl protecting group. In certainembodiments, R^(P10) is a trialkyl silyl protecting group. In certainembodiments, R^(P10) is a t-butyldimethylsilyl protecting group. Incertain embodiments, R^(P10) is a trimethylsilyl protecting group. Incertain embodiments, R^(P10) is a triethylsilyl protecting group. Incertain embodiments, R^(P10) is a t-butyldiphenylsilyl protecting group.In certain embodiments, R^(P10) is a triisopropylsilyl protecting group.In certain embodiments, R^(P10) is a benzylic protecting group. Incertain embodiments, R^(P10) is a p-methoxybenzyl protecting group. Incertain embodiments, R^(P10) is an acyl protecting group. In certainembodiments, R^(P10) is an acetyl protecting group. In certainembodiments, R^(P10) is a benzoyl protecting group. In certainembodiments, R^(P10) is a p-nitro benzoyl protecting group. In certainembodiments, R^(P10) is a pivaloyl protecting group. In certainembodiments, R^(P10) is a t-butyl carbonate (BOC) protecting group. Incertain embodiments, R^(P10) is an acetal protecting group. In certainembodiments, R^(P10) is a tetrahydropyranyl protecting group. In certainembodiments, R^(P10) is an alkoxyalkyl protecting group. In certainembodiments, R^(P10) is an ethoxyethyl protecting group.

In certain embodiments, R^(P11) is hydrogen. In certain embodiments,R^(P11) is substituted or unsubstitituted alkyl. In certain embodiments,R^(P1) is substituted or unsubstituted C₁₋₆ alkyl. In certainembodiments, R^(P11) is substituted or unsubstituted, branched C₁₋₆alkyl. In certain embodiments, R^(P11) is unsubstituted C₁₋₆ alkyl. Incertain embodiments, R^(P11) is methyl. In certain embodiments, R^(P11)is ethyl. In certain embodiments, R^(P11) is propyl. In certainembodiments, R^(P11) is iso-propyl. In certain embodiments, R^(P11) ist-butyl. In certain embodiments, R^(P11) is an oxygen protecting group.In certain embodiments, R^(P11) is a silyl protecting group. In certainembodiments, R^(P11) is a trialkyl silyl protecting group. In certainembodiments, R^(P11) is a t-butyldimethylsilyl protecting group. Incertain embodiments, R^(P11) is a trimethylsilyl protecting group. Incertain embodiments, R^(P11) is a triethylsilyl protecting group. Incertain embodiments, R^(P11) is a t-butyldiphenylsilyl protecting group.In certain embodiments, R^(P11) is a triisopropylsilyl protecting group.In certain embodiments, R^(P11) is a benzylic protecting group. Incertain embodiments, R^(P11) is a p-methoxybenzyl protecting group. Incertain embodiments, R^(P11) is an acyl protecting group. In certainembodiments, R^(P11) is an acetyl protecting group. In certainembodiments, R^(P11) is a benzoyl protecting group. In certainembodiments, R^(P11) is a p-nitro benzoyl protecting group. In certainembodiments, R^(P11) is a pivaloyl protecting group. In certainembodiments, R^(P11) is a t-butyl carbonate (BOC) protecting group. Incertain embodiments, R^(P11) is an acetal protecting group. In certainembodiments, R^(P11) is a tetrahydropyranyl protecting group. In certainembodiments, R^(P11) is an alkoxyalkyl protecting group. In certainembodiments, R^(P11) is an ethoxyethyl protecting group.

In certain embodiments, R^(P12) is hydrogen. In certain embodiments,R^(P12) is substituted or unsubstitituted alkyl. In certain embodiments,R^(P12) is substituted or unsubstituted C₁₋₆ alkyl. In certainembodiments, R¹² is substituted or unsubstituted, branched C₁₋₆ alkyl.In certain embodiments, R^(P12) is unsubstituted C₁₋₆ alkyl. In certainembodiments, R^(P12) is methyl. In certain embodiments, R^(P12) isethyl. In certain embodiments, R^(P12) is propyl. In certainembodiments, R^(P12) is iso-propyl. In certain embodiments, R^(P12) ist-butyl. In certain embodiments, R^(P12) is an oxygen protecting group.In certain embodiments, R^(P12) is a silyl protecting group. In certainembodiments, R^(P12) is a trialkyl silyl protecting group. In certainembodiments, R^(P12) is a t-butyldimethylsilyl protecting group. Incertain embodiments, R^(P12) is a trimethylsilyl protecting group. Incertain embodiments, R^(P12) is a triethylsilyl protecting group. Incertain embodiments, R^(P12) is a t-butyldiphenylsilyl protecting group.In certain embodiments, R^(P12) is a triisopropylsilyl protecting group.In certain embodiments, R^(P12) is a benzylic protecting group. Incertain embodiments, R^(P12) is a p-methoxybenzyl protecting group. Incertain embodiments, R^(P12) is an acyl protecting group. In certainembodiments, R^(P12) is an acetyl protecting group. In certainembodiments, R^(P12) is a benzoyl protecting group. In certainembodiments, R^(P12) is a p-nitro benzoyl protecting group. In certainembodiments, R^(P12) is a pivaloyl protecting group. In certainembodiments, R^(P12) is a t-butyl carbonate (BOC) protecting group. Incertain embodiments, R^(P12) is an acetal protecting group. In certainembodiments, R^(P12) is a tetrahydropyranyl protecting group. In certainembodiments, R^(P12) is an alkoxyalkyl protecting group. In certainembodiments, R^(P12) is an ethoxyethyl protecting group.

In certain embodiments, R^(P13) is hydrogen. In certain embodiments,R^(P13) is substituted or unsubstitituted alkyl. In certain embodiments,R^(P13) is substituted or unsubstituted C₁₋₆ alkyl. In certainembodiments, R^(P13) is substituted or unsubstituted, branched C₁₋₆alkyl. In certain embodiments, R^(P13) is unsubstituted C₁₋₆ alkyl. Incertain embodiments, R^(P13) is methyl. In certain embodiments, R^(P13)is ethyl. In certain embodiments, R^(P13) is propyl. In certainembodiments, R^(P13) is iso-propyl. In certain embodiments, R^(P13) ist-butyl. In certain embodiments, R^(P13) is an oxygen protecting group.In certain embodiments, R^(P13) is a silyl protecting group. In certainembodiments, R^(P13) is a trialkyl silyl protecting group. In certainembodiments, R^(P13) is a t-butyldimethylsilyl protecting group. Incertain embodiments, R^(P13) is a trimethylsilyl protecting group. Incertain embodiments, R^(P13) is a triethylsilyl protecting group. Incertain embodiments, R¹³ is a t-butyldiphenylsilyl protecting group. Incertain embodiments, R^(P13) is a triisopropylsilyl protecting group. Incertain embodiments, R^(P13) is a benzylic protecting group. In certainembodiments, R^(P13) is a p-methoxybenzyl protecting group. In certainembodiments, R^(P13) is an acyl protecting group. In certainembodiments, R^(P13) is an acetyl protecting group. In certainembodiments, R^(P13) is a benzoyl protecting group. In certainembodiments, R^(P13) is a p-nitro benzoyl protecting group. In certainembodiments, R^(P13) is a pivaloyl protecting group. In certainembodiments, R^(P13) is a t-butyl carbonate (BOC) protecting group. Incertain embodiments, R^(P13) is an acetal protecting group. In certainembodiments, R^(P13) is a tetrahydropyranyl protecting group. In certainembodiments, R^(P13) is an alkoxyalkyl protecting group. In certainembodiments, R^(P13) is an ethoxyethyl protecting group.

In certain embodiments, R^(P14) is hydrogen. In certain embodiments,R^(P14) is substituted or unsubstitituted alkyl. In certain embodiments,R^(P14) is substituted or unsubstituted C₁₋₆ alkyl. In certainembodiments, R^(P14) is substituted or unsubstituted, branched C₁₋₆alkyl. In certain embodiments, R^(P14) is unsubstituted C₁₋₆ alkyl. Incertain embodiments, R^(P14) is methyl. In certain embodiments, R^(P14)is ethyl. In certain embodiments, R^(P14) is propyl. In certainembodiments, R^(P14) is iso-propyl. In certain embodiments, R^(P14) ist-butyl. In certain embodiments, R^(P14) is an oxygen protecting group.In certain embodiments, R^(P14) is a silyl protecting group. In certainembodiments, R^(P14) is a trialkyl silyl protecting group. In certainembodiments, R^(P14) is a t-butyldimethylsilyl protecting group. Incertain embodiments, R^(P14) is a trimethylsilyl protecting group. Incertain embodiments, R^(P14) is a triethylsilyl protecting group. Incertain embodiments, R^(P14) is a t-butyldiphenylsilyl protecting group.In certain embodiments, R^(P14) is a triisopropylsilyl protecting group.In certain embodiments, R^(P14) is a benzylic protecting group. Incertain embodiments, R^(P14) is a p-methoxybenzyl protecting group. Incertain embodiments, R^(P14) is an acyl protecting group. In certainembodiments, R^(P14) is an acetyl protecting group. In certainembodiments, R^(P14) is a benzoyl protecting group. In certainembodiments, R^(P14) is a p-nitro benzoyl protecting group. In certainembodiments, R^(P14) is a pivaloyl protecting group. In certainembodiments, R^(P14) is a t-butyl carbonate (BOC) protecting group. Incertain embodiments, R^(P14) is an acetal protecting group. In certainembodiments, R^(P14) is a tetrahydropyranyl protecting group. In certainembodiments, R^(P14) is an alkoxyalkyl protecting group. In certainembodiments, R^(P14) is an ethoxyethyl protecting group.

In certain embodiments, R^(P15) is hydrogen. In certain embodiments,R^(P15) is substituted or unsubstitituted alkyl. In certain embodiments,R^(P15) is substituted or unsubstituted C₁₋₆ alkyl. In certainembodiments, R^(P15) is substituted or unsubstituted, branched C₁₋₆alkyl. In certain embodiments, R^(P15) is unsubstituted C₁₋₆ alkyl. Incertain embodiments, R^(P15) is methyl. In certain embodiments, R^(P15)is ethyl. In certain embodiments, R^(P15) is propyl. In certainembodiments, R^(P15) is iso-propyl. In certain embodiments, R^(P15) ist-butyl. In certain embodiments, R^(P15) is an oxygen protecting group.In certain embodiments, R^(P15) is a silyl protecting group. In certainembodiments, R^(P15) is a trialkyl silyl protecting group. In certainembodiments, R^(P15) is a t-butyldimethylsilyl protecting group. Incertain embodiments, R^(P15) is a trimethylsilyl protecting group. Incertain embodiments, R^(P15) is a triethylsilyl protecting group. Incertain embodiments, R^(P15) is a t-butyldiphenylsilyl protecting group.In certain embodiments, R^(P15) is a triisopropylsilyl protecting group.In certain embodiments, R^(P15) is a benzylic protecting group. Incertain embodiments, R^(P15) is a p-methoxybenzyl protecting group. Incertain embodiments, R^(P15) is an acyl protecting group. In certainembodiments, R^(P15) is an acetyl protecting group. In certainembodiments, R^(P15) is a benzoyl protecting group. In certainembodiments, R^(P15) is a p-nitro benzoyl protecting group. In certainembodiments, R^(P15) is a pivaloyl protecting group. In certainembodiments, R^(P15) is a t-butyl carbonate (BOC) protecting group. Incertain embodiments, R^(P15) is an acetal protecting group. In certainembodiments, R^(P15) is a tetrahydropyranyl protecting group. In certainembodiments, R^(P15) is an alkoxyalkyl protecting group. In certainembodiments, R^(P15) is an ethoxyethyl protecting group.

In certain embodiments, R^(P16) is hydrogen. In certain embodiments,R^(P16) is substituted or unsubstitituted alkyl. In certain embodiments,R^(P16) is substituted or unsubstituted C₁₋₆ alkyl. In certainembodiments, R^(P16) is substituted or unsubstituted, branched C₁₋₆alkyl. In certain embodiments, R^(P16) is unsubstituted C₁₋₆ alkyl. Incertain embodiments, R^(P16) is methyl. In certain embodiments, R^(P16)is ethyl. In certain embodiments, R^(P16) is propyl. In certainembodiments, R^(P16) is iso-propyl. In certain embodiments, R^(P16) ist-butyl. In certain embodiments, R^(P16) is an oxygen protecting group.In certain embodiments, R^(P16) is a silyl protecting group. In certainembodiments, R^(P16) is a trialkyl silyl protecting group. In certainembodiments, R^(P16) is a t-butyldimethylsilyl protecting group. Incertain embodiments, R^(P16) is a trimethylsilyl protecting group. Incertain embodiments, R^(P16) is a triethylsilyl protecting group. Incertain embodiments, R^(P16) is a t-butyldiphenylsilyl protecting group.In certain embodiments, R^(P16) is a triisopropylsilyl protecting group.In certain embodiments, R^(P16) is a benzylic protecting group. Incertain embodiments, R^(P16) is a p-methoxybenzyl protecting group. Incertain embodiments, R^(P16) is an acyl protecting group. In certainembodiments, R^(P16) is an acetyl protecting group. In certainembodiments, R^(P16) is a benzoyl protecting group. In certainembodiments, R^(P16) is a p-nitro benzoyl protecting group. In certainembodiments, R^(P16) is a pivaloyl protecting group. In certainembodiments, R^(P16) is a t-butyl carbonate (BOC) protecting group. Incertain embodiments, R^(P16) is an acetal protecting group. In certainembodiments, R^(P16) is a tetrahydropyranyl protecting group. In certainembodiments, R^(P16) is an alkoxyalkyl protecting group. In certainembodiments, R^(P16) is an ethoxyethyl protecting group.

Groups R^(T1), R^(T2), R^(T3), and R^(T5)

As generally described herein, R^(T1), R^(T2), R^(T3), and R^(T5) areeach independently hydrogen, halogen, or substituted or unsubstitutedalkyl.

In certain embodiments, R^(T1) is hydrogen. In certain embodiments,R^(T1) is halogen (e.g., —F, —Cl, —Br, or —I). In certain embodiments,R^(T1) is fluorine. In certain embodiments, R^(T1) is chlorine. Incertain embodiments, R^(T1) is substituted or unsubstitituted alkyl. Incertain embodiments, R^(T1) is substituted or unsubstituted C₁₋₆ alkyl.In certain embodiments, R^(T1) is substituted or unsubstituted, branchedC₁₋₆ alkyl. In certain embodiments, R^(T1) is unsubstituted C₁₋₆ alkyl.In certain embodiments, R^(T1) is methyl. In certain embodiments, R^(T1)is methyl; and the carbon to which the methyl group is attached is inthe (S)-configuration. In certain embodiments, R¹ is methyl; and thecarbon to which the methyl group is attached is in the(R)-configuration. In certain embodiments, R^(T1) is ethyl. In certainembodiments, R^(T1) is propyl. In certain embodiments, R^(T1) isiso-propyl. In certain embodiments, R^(T1) is butyl. In certainembodiments, R^(T1) is t-butyl.

In certain embodiments, the stereochemical configuration of the carbonatom to which R^(T1) is attached is (S). In certain embodiments, thestereochemical configuration of the carbon atom to which R^(T1) isattached is (R).

In certain embodiments, R^(T2) is hydrogen. In certain embodiments,R^(T2) is halogen (e.g., —F, —Cl, —Br, or —I). In certain embodiments,R^(T2) is fluorine. In certain embodiments, R^(T2) is chlorine. Incertain embodiments, R^(T2) is substituted or unsubstitituted alkyl. Incertain embodiments, R^(T2) is substituted or unsubstituted C₁₋₆ alkyl.In certain embodiments, R^(T2) is substituted or unsubstituted, branchedC₁₋₆ alkyl. In certain embodiments, R^(T2) is unsubstituted C₁₋₆ alkyl.In certain embodiments, R^(T2) is methyl. In certain embodiments, R^(T2)is methyl; and the carbon to which the methyl group is attached is inthe (S)-configuration. In certain embodiments, R^(T2) is methyl; and thecarbon to which the methyl group is attached is in the(R)-configuration. In certain embodiments, R^(T2) is ethyl. In certainembodiments, R^(T2) is propyl. In certain embodiments, R^(T2) isiso-propyl. In certain embodiments, R^(T2) is butyl. In certainembodiments, R^(T2) is t-butyl.

In certain embodiments, the stereochemical configuration of the carbonatom to which R^(T2) is attached is (S). In certain embodiments, thestereochemical configuration of the carbon atom to which R^(T2) isattached is (R).

In certain embodiments, R^(T3) is hydrogen. In certain embodiments,R^(T3) is halogen (e.g., —F, —Cl, —Br, or —I). In certain embodiments,R^(T3) is fluorine. In certain embodiments, R^(T) is chlorine. Incertain embodiments, R^(T3) is substituted or unsubstitituted alkyl. Incertain embodiments, R^(T3) is substituted or unsubstituted C₁₋₆ alkyl.In certain embodiments, R^(T3) is substituted or unsubstituted, branchedC₁₋₆ alkyl. In certain embodiments, R^(T3) is unsubstituted C₁₋₆ alkyl.In certain embodiments, R^(T3) is methyl. In certain embodiments, R¹³ ismethyl; and the carbon to which the methyl group is attached is in the(S)-configuration. In certain embodiments, R^(T3) is methyl; and thecarbon to which the methyl group is attached is in the(R)-configuration. In certain embodiments, R^(T3) is ethyl. In certainembodiments, R³ is propyl. In certain embodiments, R^(T3) is iso-propyl.In certain embodiments, R^(T3) is butyl. In certain embodiments, R^(T3)is t-butyl.

In certain embodiments, the stereochemical configuration of the carbonatom to which R^(T3) is attached is (S). In certain embodiments, thestereochemical configuration of the carbon atom to which R^(T3) isattached is (R).

In certain embodiments, R^(T5) is hydrogen. In certain embodiments,R^(T5) is halogen (e.g., —F, —Cl, —Br, or —I). In certain embodiments,R^(T5) is fluorine. In certain embodiments, R^(T5) is chlorine. Incertain embodiments, R^(T5) is substituted or unsubstitituted alkyl. Incertain embodiments, R^(T5) is substituted or unsubstituted C₁₋₆ alkyl.In certain embodiments, R^(T5) is substituted or unsubstituted, branchedC₁₋₆ alkyl. In certain embodiments, R^(T5) is unsubstituted C₁₋₆ alkyl.In certain embodiments, R^(T5) is methyl. In certain embodiments, R^(T5)is methyl; and the carbon to which the methyl group is attached is inthe (S)-configuration. In certain embodiments, R^(T5) is methyl; and thecarbon to which the methyl group is attached is in the(R)-configuration. In certain embodiments, R^(T5) is ethyl. In certainembodiments, R^(T5) is propyl. In certain embodiments, R^(T5) isiso-propyl. In certain embodiments, R^(T5) is butyl. In certainembodiments, R^(T5) is t-butyl.

In certain embodiments, the stereochemical configuration of the carbonatom to which R^(T5) is attached is (S). In certain embodiments, thestereochemical configuration of the carbon atom to which R^(T5) isattached is (R).

In certain embodiments, all of R^(T1), R^(T2), R^(T3), and R^(T5) areindependently substituted or unsubstituted alkyl. In certainembodiments, all of R^(T1), R^(T2), R^(T3), and R^(T5) are independentlysubstituted or unsubstituted C₁₋₆ alkyl. In certain embodiments, all ofR^(T1), R^(T2), R^(T3), and R^(T5) are independently substituted orunsubstituted, branched C₁₋₆ alkyl. In certain embodiments, all ofR^(T1), R^(T2), R^(T3), and R^(T5) are independently unsubstituted C₁₋₆alkyl. In certain embodiments, all of R^(T1), R^(T2), R^(T3), and R^(T5)are methyl. In certain embodiments, the stereochemical configuration ofthe carbon atom to which each of R^(T1), R^(T2), and R^(T3) is attachedis (S); and the stereochemical configuration of the carbon atom to whichR^(T5) is attached is (R). In certain embodiments, the stereochemicalconfiguration of the carbon atom to which each of R^(T1), R^(T2), andR^(T3) is attached is (S); the stereochemical configuration of thecarbon atom to which R^(T5) is attached is (R); and all of R^(T1),R^(T2), R^(T3), and R^(T5) are methyl.

Groups R^(T4) and R^(T6)

As generally described herein, R^(T4) and R^(T6) are each independentlyhydrogen, halogen, or substituted or unsubstituted alkyl, or two R^(T4)groups can be taken together to form a

group. In certain embodiments, at least one R^(T4) is hydrogen. Incertain embodiments, both of R^(T4) are hydrogen. In certainembodiments, at least one R^(T4) is halogen (e.g., —F, —Cl, —Br, or —I).In certain embodiments, at least one R^(T4) is fluorine. In certainembodiments, at least one R^(T4) is chlorine. In certain embodiments, atleast one R^(T4) is substituted or unsubstitituted alkyl. In certainembodiments, at least one R^(T4) is substituted or unsubstituted C₁₋₆alkyl. In certain embodiments, at least one R^(T4) is substituted orunsubstituted, branched C₁₋₆ alkyl. In certain embodiments, at least oneR^(T4) is unsubstituted C₁₋₆ alkyl. In certain embodiments, at least oneR^(T4) is methyl. In certain embodiments, at least one R^(T4) is methyl;and the carbon to which the methyl group is attached is in the(S)-configuration. In certain embodiments, at least one R^(T4) ismethyl; and the carbon to which the methyl group is attached is in the(R)-configuration. In certain embodiments, both of R^(T4) are methyl. Incertain embodiments, at least one R^(T4) is ethyl. In certainembodiments, at least one R^(T4) is propyl. In certain embodiments, atleast one R^(T4) is butyl. In certain embodiments, at least one R^(T4)is t-butyl. In certain embodiments, the stereochemical configuration ofthe carbon atom to which R^(T4) is attached is (S). In certainembodiments, the stereochemical configuration of the carbon atom towhich R^(T4) is attached is (R). In certain embodiments, two R^(T4)groups are taken together to form a

group.

In certain embodiments, at least one R^(T6) is hydrogen. In certainembodiments, both of R^(T6) are hydrogen. In certain embodiments, atleast one R^(T6) is halogen (e.g., —F, —Cl, —Br, or —I). In certainembodiments, at least one R^(T6) is fluorine. In certain embodiments, atleast one R^(T6) is chlorine. In certain embodiments, at least oneR^(T6) is substituted or unsubstitituted alkyl. In certain embodiments,at least one R^(T6) is substituted or unsubstituted C₁₋₆ alkyl. Incertain embodiments, at least one R^(T6) is substituted orunsubstituted, branched C₁₋₆ alkyl. In certain embodiments, at least oneR^(T6) is unsubstituted C₁₋₆ alkyl. In certain embodiments, at least oneR^(T6) is methyl. In certain embodiments, at least one R^(T6) is methyl;and the carbon to which the methyl group is attached is in the(S)-configuration. In certain embodiments, at least one R^(T6) ismethyl; and the carbon to which the methyl group is attached is in the(R)-configuration. In certain embodiments, both of R^(T6) are methyl. Incertain embodiments, at least one R^(T6) is ethyl. In certainembodiments, at least one R^(T6) is propyl. In certain embodiments, atleast one R^(T6) is butyl. In certain embodiments, at least one R^(T6)is t-butyl. In certain embodiments, the stereochemical configuration ofthe carbon atom to which R^(T6) is attached is (S). In certainembodiments, the stereochemical configuration of the carbon atom towhich R^(T6) is attached is (R). In certain embodiments, two R^(T6)groups are taken together to form a

group.

In certain embodiments, two R^(T4) groups are taken together to form a

group; and two R^(T6) groups are taken together to form a

group.Groups R^(TX), R^(TY), R^(TX1), R^(TY1), and R^(TXY)

As generally described herein, R^(TX) is hydrogen or —OR^(TX1), whereinR^(TX1) is hydrogen, substituted or unsubstituted alkyl, or an oxygenprotecting group; R^(T) is hydrogen or —OR^(TY1), wherein R^(TY1) ishydrogen, substituted or unsubstituted alkyl, or an oxygen protectinggroup; and R^(TX) and R^(TY) can be taken with their intervening atomsto form a substituted or unsubstituted heterocyclic ring.

In certain embodiments, the stereochemical configuration of the carbonatom to which R^(TX) is attached is (S). In certain embodiments, thestereochemical configuration of the carbon atom to which R^(TX) isattached is (R).

In certain embodiments, the stereochemical configuration of R^(TY) is(S). In certain embodiments, the stereochemical configuration of R^(TY)is (R).

In certain embodiments, R^(TX) is hydrogen. In certain embodiments,R^(TX) is —OR^(TX1). In certain embodiments, R^(TY) is hydrogen. Incertain embodiments, R^(TY) is —OR^(TY1). In certain embodiments, R^(TX)and R^(TY) are hydrogen. In certain embodiments, one of R^(TX) andR^(TY) is hydrogen. In certain embodiments, R^(TX) is hydrogen, andR^(TY) is —OR^(TY1). In certain embodiments, R^(TY) is hydrogen, andR^(TX) is —OR^(TX1). In certain embodiments, each of R^(TX) is—OR^(TX1); and R^(TY) is —OR^(TY1). In certain embodiments, R^(TX) is—OR^(TX1); R^(TY) is —OR^(TY1); and R^(TX1) and R^(TX1) are takentogether with the intervening atoms to form an optionally substitutedheterocyclic ring. In certain embodiments, R^(TX) is —OR^(TX1); R^(TY)is —OR^(TY1); and R^(TX1) and R^(TX1) are taken together with theintervening atoms to form an optionally substituted dioxane.

In certain embodiments, R^(TX1) is hydrogen. In certain embodiments,R^(TX1) is substituted or unsubstitituted alkyl. In certain embodiments,R^(TX1) is substituted or unsubstituted C₁₋₆ alkyl. In certainembodiments, R^(TX1) is substituted or unsubstituted, branched C₁₋₆alkyl. In certain embodiments, R^(TX1) is unsubstituted C₁₋₆ alkyl. Incertain embodiments, R^(TX1) is methyl. In certain embodiments, R^(TX1)is ethyl. In certain embodiments, R^(TX1) is propyl. In certainembodiments, R^(TX1) is iso-propyl. In certain embodiments, R^(TX1) ist-butyl. In certain embodiments, R^(TX1) is an oxygen protecting group.In certain embodiments, R^(TX1) is a silyl protecting group. In certainembodiments, R^(TX1) is a trialkyl silyl protecting group. In certainembodiments, R^(TX1) is a t-butyldimethylsilyl protecting group. Incertain embodiments, R^(TX1) is a trimethylsilyl protecting group. Incertain embodiments, R^(TX1) is a triethylsilyl protecting group. Incertain embodiments, R^(TX1) is a t-butyldiphenylsilyl protecting group.In certain embodiments, R^(TX1) is a triisopropylsilyl protecting group.In certain embodiments, R^(TX1) is a benzylic protecting group. Incertain embodiments, R^(TX1) is a p-methoxybenzyl protecting group. Incertain embodiments, R^(TX1) is an acyl protecting group. In certainembodiments, R^(TX1) is an acetyl protecting group. In certainembodiments, R^(TX1) is a benzoyl protecting group. In certainembodiments, R^(TX1) is a p-nitro benzoyl protecting group. In certainembodiments, R^(TX1) is a pivaloyl protecting group. In certainembodiments, R^(TX1) is a t-butyl carbonate (BOC) protecting group. Incertain embodiments, R^(TX1) is an acetal protecting group. In certainembodiments, R^(TX1) is a tetrahydropyranyl protecting group. In certainembodiments, R^(TX1) is an alkoxyalkyl protecting group. In certainembodiments, R^(TX1) is an ethoxyethyl protecting group.

In certain embodiments, R^(TY1) is hydrogen. In certain embodiments,R^(TY1) is substituted or unsubstitituted alkyl. In certain embodiments,R^(TY1) is substituted or unsubstituted C₁₋₆ alkyl. In certainembodiments, R^(TY1) is substituted or unsubstituted, branched C₁₋₆alkyl. In certain embodiments, R^(TY1) is unsubstituted C₁₋₆ alkyl. Incertain embodiments, R^(TY1) is methyl. In certain embodiments, R^(TY1)is ethyl. In certain embodiments, R^(TY1) is propyl. In certainembodiments, R^(TY1) is iso-propyl. In certain embodiments, R^(TY1) isi-butyl. In certain embodiments, R^(TY1) is an oxygen protecting group.In certain embodiments, R^(TY1) is a silyl protecting group. In certainembodiments, R^(TY1) is a trialkyl silyl protecting group. In certainembodiments, R^(TY1) is a t-butyldimethylsilyl protecting group. Incertain embodiments, R^(TY1) is a trimethylsilyl protecting group. Incertain embodiments, R^(TY1) is a triethylsilyl protecting group. Incertain embodiments, R^(TY1) is a t-butyldiphenylsilyl protecting group.In certain embodiments, R^(TY1) is a triisopropylsilyl protecting group.In certain embodiments, R^(TY1) is a benzylic protecting group. Incertain embodiments, R^(TY1) is a p-methoxybenzyl protecting group. Incertain embodiments, R^(TY1) is an acyl protecting group. In certainembodiments, R^(TY1) is an acetyl protecting group. In certainembodiments, R^(TY1) is a benzoyl protecting group. In certainembodiments, R^(TY1) is a p-nitro benzoyl protecting group. In certainembodiments, R^(TY1) is a pivaloyl protecting group. In certainembodiments, R^(TY1) is a t-butyl carbonate (BOC) protecting group. Incertain embodiments, R^(TY1) is an acetal protecting group. In certainembodiments, R^(TY1) is a tetrahydropyranyl protecting group. In certainembodiments, R^(TY1) is an alkoxyalkyl protecting group. In certainembodiments, R^(TY1) is an ethoxyethyl protecting group.

In certain embodiments, both R^(TX1) and R^(TY1) are hydrogen.

In certain embodiments, the stereochemical configuration of the carbonatom to which R^(TX) is attached is (S). In certain embodiments, thestereochemical configuration of the carbon atom to which R^(TX) isattached is (R). In certain embodiments, the stereochemicalconfiguration of the carbon atom to which R^(TY) is attached is (S). Incertain embodiments, the stereochemical configuration of the carbon atomto which R^(TY) is attached is (R).

In certain embodiments, the stereochemical configuration of the carbonatom to which R^(TX) is attached is (S); and the stereochemicalconfiguration of the carbon atom to which R^(TY) is attached is (S). Incertain embodiments, the stereochemical configuration of the carbon atomto which R^(TX) is attached is (R); and the stereochemical configurationof the carbon atom to which R^(TY) is attached is (R). In certainembodiments, the stereochemical configuration of the carbon atom towhich R^(TX) is attached is (S); and the stereochemical configuration ofthe carbon atom to which R^(TY) is attached is (R). In certainembodiments, the stereochemical configuration of the carbon atom towhich R^(TX) is attached is (R); and the stereochemical configuration ofthe carbon atom to which R^(TY) is attached is (S).

In certain embodiments, R^(TX) and R^(TY) are taken with theirintervening atoms to form a substituted or unsubstituted heterocyclicring. In certain embodiments, R^(TX) and R^(TY) form a substituted orunsubstituted, 5-membered heterocyclic ring. In certain embodiments,R^(x) and R^(TY) form a substituted or unsubstituted, 6-memberedheterocyclic ring. In certain embodiments, R^(TX) and R^(TY) form asubstituted or unsubstituted dioxolane. In certain embodiments, R^(TX)and R^(TY) form a mono-substituted dioxolane. In certain embodiments,R^(TX) and R^(TY) form a dioxolane substituted with one instance of asubstituted or unsubstituted phenyl ring. In certain embodiments, R^(TX)and R^(TY) form a dioxolane substituted with one instance of amono-substituted phenyl ring. In certain embodiments, R^(TX) and R^(TY)form a substituted or unsubstituted dioxane.

Group R^(T7)

In certain embodiments, R^(T7) is hydrogen. In certain embodiments,R^(T7) is substituted or unsubstitituted alkyl. In certain embodiments,R^(T7) is substituted or unsubstituted C₁₋₆ alkyl. In certainembodiments, R^(T7) is substituted or unsubstituted, branched C₁₋₆alkyl. In certain embodiments, R^(T7) is unsubstituted C₁₋₆ alkyl. Incertain embodiments, R^(T7) is methyl. In certain embodiments, R^(T7) isethyl. In certain embodiments, R^(T7) is propyl. In certain embodiments,R^(T7) is iso-propyl. In certain embodiments, R^(T7) is t-butyl. Incertain embodiments, R^(T7) is an oxygen protecting group. In certainembodiments, R^(T7) is a silyl protecting group. In certain embodiments,R^(T7) is a trialkyl silyl protecting group. In certain embodiments,R^(T7) is a t-butyldimethylsilyl protecting group. In certainembodiments, R^(T7) is a trimethylsilyl protecting group. In certainembodiments, R^(T7) is a triethylsilyl protecting group. In certainembodiments, R^(T7) is a t-butyldiphenylsilyl protecting group. Incertain embodiments, R^(T7) is a triisopropylsilyl protecting group. Incertain embodiments, R^(T7) is a benzylic protecting group. In certainembodiments, R^(T7) is a p-methoxybenzyl protecting group. In certainembodiments, R^(T7) is an acyl protecting group. In certain embodiments,R^(T7) is an acetyl protecting group. In certain embodiments, R^(T7) isa benzoyl protecting group. In certain embodiments, R^(T7) is a p-nitrobenzoyl protecting group. In certain embodiments, R^(T7) is a pivaloylprotecting group. In certain embodiments, R⁷ is a t-butyl carbonate(BOC) protecting group. In certain embodiments, R⁷ is an acetalprotecting group. In certain embodiments, R^(T7) is a tetrahydropyranylprotecting group. In certain embodiments, R^(T7) is an alkoxyalkylprotecting group. In certain embodiments, R^(T7) is an ethoxyethylprotecting group.

Groups X^(T), R^(Z1), R^(Z4), R^(Z5), R^(Z1a), R^(4a), and R^(Z5a)

As generally described herein, XT is halogen (e.g., —F, —Cl, —Br, or—I). In certain embodiments, X^(T) is bromine. In certain embodiments,XT is iodine.

As generally described herein, R^(Z1) is —CO₂R^(Z1a), wherein R^(Z1a) ishydrogen, substituted or unsubstituted alkyl, or an oxygen protectinggroup. In certain embodiments, R^(Z1a) is hydrogen. In certainembodiments, R^(Z1a) is substituted or unsubstitituted alkyl. In certainembodiments, R^(Z1a) is substituted or unsubstituted C₁₋₆ alkyl. Incertain embodiments, R^(Z1a) is substituted or unsubstituted, branchedC₁₋₆ alkyl. In certain embodiments, R^(Z1a) is unsubstituted C₁₋₆ alkyl.In certain embodiments, R^(Z1a) is methyl. In certain embodiments,R^(Z1a) is ethyl. In certain embodiments, R^(Z1a) is propyl. In certainembodiments, R^(Z1a) is iso-propyl. In certain embodiments, R^(Z1a) ist-butyl. In certain embodiments, R^(Z1a) is an oxygen protecting group.In certain embodiments, R^(Z1a) is a silyl protecting group. In certainembodiments, R^(Z1a) is a trialkyl silyl protecting group. In certainembodiments, R^(Z1a) is a t-butyldimethylsilyl protecting group. Incertain embodiments, R^(Z1a) is a trimethylsilyl protecting group. Incertain embodiments, R^(Z1a) is a triethylsilyl protecting group. Incertain embodiments, R^(z1a) is a t-butyldiphenylsilyl protecting group.In certain embodiments, R^(Z1a) is a triisopropylsilyl protecting group.In certain embodiments, R^(Z1a) is a benzylic protecting group. Incertain embodiments, R^(Z1a) is a p-methoxybenzyl protecting group. Incertain embodiments, R^(Z1a) is an acyl protecting group. In certainembodiments, R^(Z1a) is an acetyl protecting group. In certainembodiments, R^(Z1a) is a benzoyl protecting group. In certainembodiments, R^(Z1a) is a p-nitro benzoyl protecting group. In certainembodiments, R^(Z1a) is a pivaloyl protecting group. In certainembodiments, R^(Z1a) is a t-butyl carbonate (BOC) protecting group. Incertain embodiments, R^(Z1a) is an acetal protecting group. In certainembodiments, R^(Z1a) is a tetrahydropyranyl protecting group. In certainembodiments, R^(Z1a) is an alkoxyalkyl protecting group. In certainembodiments, R^(Z1a) is an ethoxyethyl protecting group.

As generally described herein, R^(Z4) is —CH₂OR^(Z4a) or —CHO, whereinR^(Z4a) is hydrogen, substituted or unsubstituted alkyl, optionallysubstituted acyl, or an oxygen protecting group. In certain embodiments,R^(Z4a) is hydrogen. In certain embodiments, R^(Z4a) is substituted orunsubstitituted alkyl. In certain embodiments, R^(Z4a) is substituted orunsubstituted C₁₋₆ alkyl. In certain embodiments, R^(Z4a) is substitutedor unsubstituted, branched C₁₋₆ alkyl. In certain embodiments, R^(Z4a)is unsubstituted C₁₋₆ alkyl. In certain embodiments, R^(Z4a) is methyl.In certain embodiments, R^(Z4a) is ethyl. In certain embodiments,R^(Z4a) is propyl. In certain embodiments, R^(Z4a) is iso-propyl. Incertain embodiments, R^(Z4a) is t-butyl. In certain embodiments, R^(Z4a)is an oxygen protecting group. In certain embodiments, R^(Z4a) is asilyl protecting group. In certain embodiments, R^(Z4a) is a trialkylsilyl protecting group. In certain embodiments, R^(Z4a) is at-butyldimethylsilyl protecting group. In certain embodiments, R^(Z4a)is a trimethylsilyl protecting group. In certain embodiments, R^(Z4a) isa triethylsilyl protecting group. In certain embodiments, R^(Z4a) is at-butyldiphenylsilyl protecting group. In certain embodiments, R^(Z4a)is a triisopropylsilyl protecting group. In certain embodiments, R^(Z4a)is a benzylic protecting group. In certain embodiments, R^(Z4a) is ap-methoxybenzyl protecting group. In certain embodiments, R^(Z4a) is anacyl protecting group. In certain embodiments, R^(Z4a) is an acetylprotecting group. In certain embodiments, R^(Z4a) is a benzoylprotecting group. In certain embodiments, R^(Z4a) is a p-nitro benzoylprotecting group. In certain embodiments, R^(Z4a) is a pivaloylprotecting group. In certain embodiments, R^(Z4a) is a t-butyl carbonate(BOC) protecting group. In certain embodiments, R^(Z4a) is an acetalprotecting group. In certain embodiments, R^(Z4a) is a tetrahydropyranylprotecting group. In certain embodiments, R^(Z4a) is an alkoxyalkylprotecting group. In certain embodiments, R^(Z4a) is an ethoxyethylprotecting group.

As generally described herein, R^(Z5) is —CO₂R^(Z5a), —CH₂OR^(Z5a), or—CHO, wherein R^(Z5a) is hydrogen, substituted or unsubstituted alkyl,optionally substituted acyl, or an oxygen protecting group. In certainembodiments, R^(Z5) is —CH₂OR^(Z5a). In certain embodiments, R^(Z5) is—CHO. In certain embodiments, R^(Z5) is —CO₂R^(Z5a). In certainembodiments, R^(Z5a) is hydrogen. In certain embodiments, R^(Z5a) issubstituted or unsubstitituted alkyl. In certain embodiments, R^(Z5a) issubstituted or unsubstituted C₁₋₆ alkyl. In certain embodiments, R^(Z5a)is substituted or unsubstituted, branched C₁₋₆ alkyl. In certainembodiments, R^(Z5) is unsubstituted C₁₋₆ alkyl. In certain embodiments,R^(Z5a) is methyl. In certain embodiments, R^(Z5) is —CH₂OR^(Z5a); andR^(Z5a) is methyl. In certain embodiments, R^(Z5a) is ethyl. In certainembodiments, R^(Z5a) is propyl. In certain embodiments, R^(Z5a) isiso-propyl. In certain embodiments, R^(Z5a) is t-butyl. In certainembodiments, R^(Z5a) is an oxygen protecting group. In certainembodiments, R^(Z5a) is a silyl protecting group. In certainembodiments, R^(Z5a) is a trialkyl silyl protecting group. In certainembodiments, R^(Z5a) is a t-butyldimethylsilyl protecting group. Incertain embodiments, R^(Z5a) is a trimethylsilyl protecting group. Incertain embodiments, R^(Z5a) is a triethylsilyl protecting group. Incertain embodiments, R^(Z5a) is a t-butyldiphenylsilyl protecting group.In certain embodiments, R^(Z5a) is a triisopropylsilyl protecting group.In certain embodiments, R^(Z5a) is a benzylic protecting group. Incertain embodiments, R^(Z5a) is a p-methoxybenzyl protecting group. Incertain embodiments, R^(Z5a) is an acyl protecting group. In certainembodiments, R^(Z5a) is an acetyl protecting group. In certainembodiments, R^(Z5a) is a benzoyl protecting group. In certainembodiments, R^(Z5a) is a p-nitro benzoyl protecting group. In certainembodiments, R^(Z5a) is a pivaloyl protecting group. In certainembodiments, R^(Z5a) is a t-butyl carbonate (BOC) protecting group. Incertain embodiments, R^(Z5a) is an acetal protecting group. In certainembodiments, R^(Z5a) is a tetrahydropyranyl protecting group. In certainembodiments, R^(Z5a) is an alkoxyalkyl protecting group. In certainembodiments, R^(Z5a) is an ethoxyethyl protecting group.

Groups R^(Z2) and R^(Z3)

As generally described herein, R^(Z2) is halogen (e.g., —F, —Cl, —Br, or—I) or a leaving group. In certain embodiments, R^(Z2) is chlorine. Incertain embodiments, R^(Z2) is bromine. In certain embodiments, R^(Z2)is iodine.

As generally described herein, R^(z3) is halogen (e.g., —F, —Cl, —Br, or—I). In certain embodiments, R^(Z3) is bromine. In certain embodiments,R^(Z3) is iodine.

Group R^(A)

As generally defined herein, each instance of R^(A) is independentlyhydrogen, optionally substituted alkyl, or an oxygen protecting group;or optionally two R^(A) are joined to together with the interveningatoms to form optionally substituted heterocyclyl. In certainembodiments, at least one of R^(A) is optionally substituted alkyl. Incertain embodiments, at least one of R^(A) is an oxygen protectinggroup. In certain embodiments, two R^(A) are joined together to formoptionally substituted heterocyclyl. In certain embodiments, two R^(A)are joined together to form optionally substituted 5-to-6 memberedheterocyclyl. In certain embodiments, two R^(A) are joined together toform optionally substituted 6-membered heterocyclyl. In certainembodiments, two R^(A) are joined together to form substituted6-membered heterocyclyl. In certain embodiments, two R^(A) are joinedtogether to form the following structure:

Group R^(B)

As generally defined herein, each instance of R^(B) is independentlyhydrogen or optionally substituted alkyl. In certain embodiments, atleast one instance of R^(B) is optionally substituted alkyl. In certainembodiments, at least one instance of R^(B) is optionally substitutedalkyl. In certain embodiments, at least one instance of R^(B) isoptionally substituted C₁₋₆ alkyl. In certain embodiments, at least oneinstance of R^(B) is optionally substituted C₁₋₃ alkyl. In certainembodiments, at least one instance of R^(B) is unsubstituted C₁₋₃ alkyl(e.g., methyl, ethyl, n-propyl, iso-propyl). In certain embodiments, atleast one instance of R^(B) is methyl. In certain embodiments, bothR^(B) are methyl.

Group R^(B)

As generally defined herein, each instance of R^(B) is independentlyhydrogen, optionally substituted alkyl, optionally substituted acyl, oran oxygen protecting group. In certain embodiments, at least oneinstance of R^(B) is optionally substituted alkyl. In certainembodiments, at least one instance of R^(B) is optionally substitutedalkyl. In certain embodiments, at least one instance of R^(B) isoptionally substituted C₁₋₆ alkyl. In certain embodiments, at least oneinstance of R^(B) is optionally substituted C₁₋₃ alkyl. In certainembodiments, at least one instance of R^(B) is unsubstituted C₁₋₃ alkyl(e.g., methyl, ethyl, n-propyl, iso-propyl). In certain embodiments, atleast one instance of R^(B) is methyl. In certain embodiments, bothR^(B) are methyl.

Group R^(PC)

As generally defined herein, each instance of R^(PC) is independentlyhydrogen, optionally substituted alkyl, optionally substituted acyl, oran oxygen protecting group. In certain embodiments, R^(PC) is optionallysubstituted alkyl. In certain embodiments, R^(PC) is optionallysubstituted alkyl. In certain embodiments, R^(PC) is optionallysubstituted C₁₋₆ alkyl. In certain embodiments, R^(PC) is optionallysubstituted C₁₋₃ alkyl. In certain embodiments, R^(PC) is unsubstitutedC₁₋₃ alkyl (e.g., methyl, ethyl, n-propyl, iso-propyl). In certainembodiments, R^(PC) is methyl.

Group R^(PC)

As generally defined herein, each instance of R^(PC) is independentlyhydrogen, optionally substituted alkyl, optionally substituted acyl, oran oxygen protecting group. In certain embodiments, R^(PC) is optionallysubstituted alkyl. In certain embodiments, R^(PC) is optionallysubstituted alkyl. In certain embodiments, R^(PC) is optionallysubstituted C₁₋₆ alkyl. In certain embodiments, R^(PC) is optionallysubstituted C₁₋₃ alkyl. In certain embodiments, R^(PC) is unsubstitutedC₁₋₃ alkyl (e.g., methyl, ethyl, n-propyl, iso-propyl). In certainembodiments, R^(PC) is methyl.

Group R^(PC)

As generally defined herein, each instance of R^(PC) is independentlyhydrogen, optionally substituted alkyl, optionally substituted acyl, oran oxygen protecting group. In certain embodiments, R^(PC) is optionallysubstituted alkyl. In certain embodiments, R^(PC) is optionallysubstituted alkyl. In certain embodiments, R^(PC) is optionallysubstituted C₁₋₆ alkyl. In certain embodiments, R^(PC) is optionallysubstituted C₁₋₃ alkyl. In certain embodiments, R^(PC) is unsubstitutedC₁₋₃ alkyl (e.g., methyl, ethyl, n-propyl, iso-propyl). In certainembodiments, R^(PC) is methyl.

Group X³

As generally defined herein, X³ is a halogen (e.g., —F, —Cl, —Br, or —I)or a leaving group. In certain embodiments, X³ is a fluorine. In certainembodiments, X³ is a chlorine. In certain embodiments, X³ is a bromine.In certain embodiments, X³ is an iodine. In certain embodiments, X³ is aleaving group.

Compounds

In another aspect, provided herein are intermediates in the synthesis ofhalichondrins A, B, and C, and analogs thereof. In another aspect,provided herein are compounds of Formula (I-b-6):

and salts, solvates, hydrates, polymorphs, co-crystals, tautomers,stereoisomers, and isotopically labeled derivatives thereof, whereinR^(1a), R^(1d), R^(4a), and R¹⁰ are as defined herein.

In another aspect, provided herein are compounds of Formula (I-b-7):

and salts, solvates, hydrates, polymorphs, co-crystals, tautomers,stereoisomers, and isotopically labeled derivatives thereof, whereinR^(1a), R^(1d), and R^(4a) are as defined herein.

In another aspect, provided herein are compounds of Formula (I-b-12):

and salts, solvates, hydrates, polymorphs, co-crystals, tautomers,stereoisomers, and isotopically labeled derivatives thereof, whereinR^(1a), R^(1d), R^(4a), R^(4b), and R^(4c) are as defined herein.

In another aspect, provided herein are compounds of Formula (III-2):

and salts, solvates, hydrates, polymorphs, co-crystals, tautomers,stereoisomers, and isotopically labeled derivatives thereof, whereinR^(T3), R^(P5), R^(T5), R^(Z5a), R^(P4), and R^(Z4a) are as definedherein.

In another aspect, provided herein are compounds of Formula (III-3):

and salts, solvates, hydrates, polymorphs, co-crystals, tautomers,stereoisomers, and isotopically labeled derivatives thereof, whereinR^(T3), R^(P5), R^(T5), and R^(Z4a) are as defined herein.

In another aspect, provided herein are compounds of Formula (III-4):

and salts, solvates, hydrates, polymorphs, co-crystals, tautomers,stereoisomers, and isotopically labeled derivatives thereof, whereinR^(T3), R^(P5), R^(T5), R^(Z5a), R^(A), and R^(B) are as defined herein.

In another aspect, provided herein are compounds of Formula (III-5):

and salts, solvates, hydrates, polymorphs, co-crystals, tautomers,stereoisomers, and isotopically labeled derivatives thereof, whereinR^(T3), R^(P5), and R^(B) are as defined herein.

In another aspect, provided herein are compounds of Formula (III-8):

and salts, solvates, hydrates, polymorphs, co-crystals, tautomers,stereoisomers, and isotopically labeled derivatives thereof, whereinR^(T3), R^(T5), and R^(Z5a) are as defined herein.

In another aspect, provided herein are compounds of Formula (III-9):

and salts, solvates, hydrates, polymorphs, co-crystals, tautomers,stereoisomers, and isotopically labeled derivatives thereof, whereinR^(T3), R^(T5), R^(B), and R^(Z5a) are as defined herein.

In another aspect, provided herein are compounds of Formula (III-10):

and salts, solvates, hydrates, polymorphs, co-crystals, tautomers,stereoisomers, and isotopically labeled derivatives thereof, whereinR^(T3), R^(T5), and R^(B) are as defined herein.

In another aspect, provided herein are compounds of Formula (III-11):

and salts, solvates, hydrates, polymorphs, co-crystals, tautomers,stereoisomers, and isotopically labeled derivatives thereof, whereinR^(T3), R^(T5), R^(P5), and R^(B) are as defined herein.

In another aspect, provided herein are compounds of Formula (TD-1):

and salts, solvates, hydrates, polymorphs, co-crystals, tautomers,stereoisomers, and isotopically labeled derivatives thereof, whereinR^(Z4), R^(P4), R^(T3), R^(P5), R^(Z1), R^(T4), R^(T5), R^(T6), R^(TX),and R^(TY) are as defined herein. In certain embodiments of Formula(TD-1), R^(TX) is hydrogen, and R^(TY) is —OR^(TY), wherein R^(TY) is asdefined herein. In certain embodiments of Formula (TD-1), R^(TY) ishydrogen, and R^(TX) is —OR^(TX1), wherein R^(TX1) is as defined herein.In certain embodiments of Formula (TD-1), R^(TY) is OR^(TX1), and R^(TX)is —OR^(TX1), wherein R^(TX1) and R^(TY1) are as defined herein.

In another aspect, provided herein are compounds of Formula (TE-1):

and salts, solvates, hydrates, polymorphs, co-crystals, tautomers,stereoisomers, and isotopically labeled derivatives thereof, whereinR^(Z4), R^(P4), R^(T3), R^(T4), R^(T5), R^(T6), R^(TX), and R^(TY) areas defined herein. In certain embodiments of Formula (TE-1), R^(TX) ishydrogen, and R^(TY) is —OR^(TY1), wherein R^(TY1) is as defined herein.In certain embodiments of Formula (TE-1), R^(TY) is hydrogen, and R^(TX)is —OR^(TX1), wherein R^(TX1) is as defined herein. In certainembodiments of Formula (TE-1), R^(TY) is —OR^(TX1), and R^(TX) is—OR^(TX1), wherein R^(TX1) and R^(TY1) are as defined herein.

In another aspect, provided herein are compounds of Formula (TF-1):

and salts, solvates, hydrates, polymorphs, co-crystals, tautomers,stereoisomers, and isotopically labeled derivatives thereof, whereinR^(P1), R^(P2), R^(P3), R^(P7), R^(T1), R^(T2), R^(P6), R^(P4), R^(T3),R^(T4), R^(T5), R^(T6), R^(TX), and R^(TY) are as defined herein. Incertain embodiments of Formula (TF-1), R^(TX) is hydrogen, and R^(TY) is—OR^(TY1), wherein R^(TY1) is as defined herein. In certain embodimentsof Formula (TF-1), R^(TY) is hydrogen, and R^(TX) is —OR^(TX1), whereinR^(TX1) is as defined herein. In certain embodiments of Formula (TF-1),R^(TY) is —OR^(TX1), and R^(TX) is —OR^(TX1), wherein R^(TX1) andR^(TY1) are as defined herein.

In another aspect, provided herein are compounds of Formula (TG-1):

and salts, solvates, hydrates, polymorphs, co-crystals, tautomers,stereoisomers, and isotopically labeled derivatives thereof, whereinR^(T7), R^(P8), R^(P9), R^(T1), R^(T2), R^(P10), R^(P11), R^(T3),R^(T4), R^(T5), R^(T6), R^(TX), and R^(TY) are as defined herein. Incertain embodiments of Formula (TG-1), R^(TX) is hydrogen, and R^(TY) is—OR^(TY1), wherein R^(TY1) is as defined herein. In certain embodimentsof Formula (TG-1), R^(TY) is hydrogen, and R^(TX) is —OR^(TX1), whereinR^(TX1) is as defined herein. In certain embodiments of Formula (TG-1),R^(TY) is —OR^(TX1), and R^(TX) is —OR^(TX1), wherein R^(TX1) andR^(TY1) are as defined herein.

In another aspect, provided herein are compounds of Formula (TH-1):

and salts, solvates, hydrates, polymorphs, co-crystals, tautomers,stereoisomers, and isotopically labeled derivatives thereof, whereinR^(P13), R^(P12), R^(P14), R^(T1), R^(T2), R^(P16), R^(P15), R^(T3),R^(T4), R^(T5), R^(T6), R^(TX), and R^(TY) are as defined herein. Incertain embodiments of Formula (TH-1), R^(TX) is hydrogen, and R^(TY) is—OR^(TY1), wherein R^(TY1) is as defined herein. In certain embodimentsof Formula (TH-1), R^(TY) is hydrogen, and R^(TX) is —OR^(TX1), whereinR^(TX1) is as defined herein. In certain embodiments of Formula (TH-1),R^(TY) is —OR^(TX1), and R^(TX) is —OR^(TX1), wherein R^(TX1) andR^(TY1) are as defined herein.

EXAMPLES

In order that the invention described herein may be more fullyunderstood, the following Examples are set forth. The synthetic andbiological examples described in this Application are offered toillustrate the compounds, pharmaceutical compositions, and methodsprovided herein and are not to be construed in any way as limiting theirscope.

General Procedures and Methods

NMR spectra were recorded on a Varian Inova 600 MHz, 500 MHzspectrometer. Chemical shifts are reported in parts per million (ppm).For ¹H NMR spectra (CDCl₃ and C₆D₆), the residual solvent peak was usedas the internal reference (7.26 ppm in CDCl₃; 7.16 ppm in C₆D₆), whilethe central solvent peak as the reference (77.0 ppm in CDCl₃, 128.0 ppmin C₆D₆) for ¹³C NMR spectra. Optical rotations were measured at 20° C.using a Perkin-Elmer 241 polarimeter. Analytical and semi-preparativethin layer chromatography (TLC) was performed with E. Merck pre-coatedTLC plates, silica gel 60 F₂₅₄, layer thickness 0.50 and 1.00 mm,respectively. TLC plates were visualized by staining with p-anisaldehydestain. Flash chromatography separations were performed on E. MerckKieselgel 60 (230-400) mesh silica gel. High performance liquidchromatography (HPLC) was carried out with Waters 1525 on a UVspectrophotometric detector (254 nm, Waters 2489) to which a 21.2×250 mmsize column (Zobrax SIL) packed with silica gel (7.0 μm) was attached.All moisture sensitive reactions were conducted under an inertatmosphere. Reaction vessels were oven-dried and allowed to cool undervacuum (1 mmHg). Reagents and solvents were commercial grade and wereused as supplied, unless otherwise noted.

Example 1. Selective Activation/Coupling of Poly-HalogenatedNucleophiles in Ni/Cr-Mediated Reactions: Synthesis of C1-C19 BuildingBlock of Halichondrin Bs

The compounds provided herein can be prepared from readily availablestarting materials using the following general methods and procedures.It will be appreciated that where typical or preferred processconditions (i.e., reaction temperatures, times, mole ratios ofreactants, solvents, pressures, etc.) are given, other processconditions can also be used unless otherwise stated. Optimum reactionconditions may vary with the particular reactants or solvents used, butsuch conditions can be determined by those skilled in the art by routineoptimization procedures.

Synthesis Outlined in FIG. 7 Synthesis of Model Trans-Haloenone(Taniguchi, M.; Kobayashi, S.; Nakagawa, M.; Hino, T.; Kishi, Y.Tetrahedron Lett. 1986, 27, 4763.)

To a solution of trimethylsilyl acetylene (5.4 g, 55 mmol) in THF (140mL) was added slowly n-butyllithium (2.5 M in hexanes, 21 mL, 52.5 mmol)at −78° C. for about 30 min. After 1 h, a solution of octanal (6.4 g, 50mmol) in THF (60 mL) was added over another 30 min. The resultingmixture was stirred at −78° C. for 2 h and then quenched by saturatedNH₄Cl solution (100 mL) and extracted with EtOAc (150 mL×3). Theextracts were washed with brine (300 mL), dried over MgSO₄, and thenpassed through a pad of silica gel (40 g; hexanes/EtOAc=10:1→4:1) andthe eluent was concentrated under reduced pressure, to give the productas light yellow liquid. This material was immediately used for the nextstep without further purification.

To a solution of crude propargyl alcohol product from previous step inmethanol (200 mL) was added K₂CO₃ (13.8 g, 100 mmol) at 0° C. After 6 h,to the reaction mixture was added 100 mL water to quench the reaction.The reaction mixture was extracted with EtOAc (100 mL×3) and thecombined organic layer was washed with 200 mL brine, dried overanhydrous MgSO₄, and concentrated under reduced pressure. The residuewas purified by flash column chromatography on silica gel with eluent ofhexanes/EtOAc (10:1 to 3:1) to give pure alcohol product XS-1 as lightyellow oil in 6.6 g.

Jones Oxidation:

To a solution of terminal propargyl alcohol XS-1 (6.6 g, 21.8 mmol) inacetone (106 mL) was added dropwise 30 mL of freshly prepared Jones'reagent ((a) Bowden, K.; Heilbron, I. M.; Jones, E. R. H.; Weedon, B. C.L. J. Chem. Soc. 1946, 39, (b) Eisenbraun, E. J. Org. Synth. 1965, 45,28). The isopropyl alcohol was added dropwise until the excess Jones'reagent was destroyed (the color of reaction mixture became deep green).Saturated NaHCO₃ solution was added in small portions, and thesuspension was stirred vigorously until the pH of the reaction mixturebecame neutral (pH=7). The suspension was filtered and the filter cakewas washed with 50 mL of acetone. The filtrate was extracted with hexane(100 mL×3) and combined organic layer was washed with 200 mL brine. Theorganic layer was dried over anhydrous MgSO₄ and concentrated underreduced pressure. The residue was purified by flash columnchromatography on silica gel with eluent of hexanes/EtOAc (10:1 to 2:1),to give 1-decyn-3-one XS-2 product as light yellow oil (6.2 g, 82% yieldin 3 steps).

HX Addition of Ynone:

To a solution of 1-decyn-3-one XS-2 (0.76 g, 5 mmol) in trifluoroaceticacid (TFA, 10 mL) was added Li, LiBr, or LiCl salt (5 mmol). Thereaction mixture was stirred for 1 h, and then poured in 20 mL saturatedNaHCO₃ solution. NaHCO₃ (solid) was added in small portions, and thesolution was stirred vigorously until the pH of reaction became neutral.The reaction mixture was extracted with Et₂O (50 mL×3) and combinedorganic extracts were washed with 50 mL of saturated NaHCO₃ solution and50 mL of brine. The organic layer was dried over anhydrous MgSO₄ anconcentrated under reduced pressure. The residue was purified by flashcolumn chromatography on silica gel with eluent of hexanes/Et₂O (100:1),to give trans-haloenone product X-9a-c as light yellow oil.

(E)-1-iododec-1-en-3-one (X-9a)

lithium salt was LiI, 87% yield; ¹H NMR (500 MHz, CDCl₃) δ: 7.80 (d,J=15.0 Hz, 1H), 7.15 (d, J=15.0 Hz, 1H), 2.50 (t, J=7.5 Hz, 2H),1.64-1.56 (m, 2H), 1.36-1.22 (m, 8H), 0.87 (t, J=7.5 Hz, 3H); ¹³C NMR(125 MHz, CDCl₃) δ: 197.6, 144.6, 98.6, 40.4, 31.6, 29.1, 29.0, 23.7,22.6, 14.0; HRMS (ESI) m/z: [M+H]⁺ calcd for C₁₀H₁₈IO, 281.0402. found,281.0408.

(E)-1-bromodec-1-en-3-one (X-9b)

lithium salt was LiBr, 85% yield; ¹H NMR (500 MHz, CDCl₃) δ: 7.51 (d,J=14.0 Hz, 1H), 6.79 (d, J=14.0 Hz, 1H), 2.50 (t, J=7.5 Hz, 2H),1.65-1.56 (m, 2H), 1.33-1.22 (m, 8H), 0.87 (t, J=7.5 Hz, 3H); ¹³C NMR(125 MHz, CDCl₃) δ: 197.5, 136.5, 125.7, 41.0, 31.6, 29.1, 29.0, 23.8,22.6, 14.0; HRMS (ESI) m/z: [M+H]⁺ calcd for C₁₀H₁₈BrO, 233.0541. found,233.0540.

(E)-1-chlorodec-1-en-3-one (X-9c)

lithium salt was LiCl, 90% yield; ¹H NMR (500 MHz, CDCl₃) δ: 7.28 (d,J=13.5 Hz, 1H), 6.52 (d, J=15.0 Hz, 1H), 2.51 (t, J=7.5 Hz, 2H),1.66-1.56 (m, 2H), 1.36-1.22 (m, 8H), 0.88 (t, J=7.5 Hz, 3H); ¹³C NMR(125 MHz, CDCl₃) δ: 197.5, 136.3, 132.3, 41.4, 31.6, 29.1, 29.0, 23.8,22.6, 14.0; HRMS (ESI) m/z: [M+H]⁺ calcd for C₁₀H₁₈ClO, 189.1046. found,189.1044.

General Procedure (A) of Asymmetric Catalytic Ni/Cr-Mediated Couplingwith Trans-Haloenone X-9a-c

To a mixture of natural sulfonamide (Guo, H.; Dong, C. G.; Kim, D. S.;Urabe, D.; Wang, J.; Kim, J. T.; Liu, X.; Sasaki, T.; Kishi, Y. J. Am.Chem. Soc. 2009, 131, 15387) X-12 (5.20 mg, 11.0 μmol), proton sponge(Aldrich, purified by sublimation; 2.36 mg, 11.0 μmol) and CrCl₂(Aldrich, 99.99% mg, 1.23 mg, 10.0 μmol) was added MeCN (Baker, ultralow water; 50 μL) in a glovebox. The mixture was stirred for 60 min atrt under nitrogen. To the second new vial were added Zr(cp)₂Cl₂(Aldrich, 98%; 43.8 mg, 0.15 mmol), Mn powder (Aldrich, 99.99%, powder;11.0 mg, 0.20 mmol), LiCl (Aldrich, anhydrous, grinded; 8.5 mg, 0.20mmol), NiCl₂. complex (Liu, X.; Li, X.; Chen, Y.; Hu, Y.; Kishi, Y. J.Am. Chem. Soc. 2012, 134, 6136) (X-13a, 1.0 μmol for 1.0 mol % or X-13b,0.05 μmol for 0.05 mol %), aldehyde X-10 (32.7 mg, 0.10 mmol) andtrans-haloenone X-9a-c (0.15 mmol). The deep green mixture in the firstvial was transferred to the second reaction vial with syringe undernitrogen. The reaction mixture was stirred under nitrogen until thereaction was completed (by TLC) about 3 h, and diluted with EtOAc (2.0mL). Florisil (ca. 50 mg) was added, and the mixture was stirred for 30min, filtered through a short silica gel pad using hexanes/EtOAc (1:1).The eluent was concentrated in vacuo to furnish the crude couplingproduct, which was purified by preparative TLC (hexanes/EtOAc=4:1) togive X-11 as yellow liquid.

(E)-1-((tert-butyldiphenylsilyl)oxy)-4-hydroxytetradec-5-en-7-one (X-11)

¹H NMR (500 MHz, CDCl₃) δ: 7.71-7.63 (m, 4H), 7.47-7.36 (m, 6H), 6.80(dd, J=15.5, 5.0 Hz, 1H), 6.34 (dd, J=16.0, 2.0 Hz, 1H), 4.44-4.32 (m,1H), 3.70 (t, J=5.0 Hz, 2H), 2.90 (d, J=4.5 Hz, 1H), 2.54 (t, J=7.5 Hz,2H), 1.87-1.78 (m, 1H), 1.74-1.58 (m, 5H), 1.38-1.19 (m, 8H), 1.06 (s,9H), 0.88 (t, J=7.0 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃) δ: 200.8, 147.6,135.6, 133.2, 129.8, 128.1, 127.7, 70.9, 64.1, 40.9, 34.1, 31.7, 29.2,29.1, 28.3, 26.8, 24.1, 22.6, 19.1, 14.1; HRMS (ESI) m/z: [M+H]⁺ calcdfor C₃₀H₄₅O₃Si, 481.3138. found, 481.3137.

Synthesis of Chiral Sulfonamide X-12

To a solution of vanillin (20.0 g, 0.13 mol) in THF (400 mL) was addedacetic anhydride Ac₂O (15 mL, 0.16 mol), Et₃N (28 mL, 0.20 mol), andDMAP (50 mg). The solution was stirred at rt for 2 h, then concentratedunder reduced pressure. 200 mL of CH₂Cl₂ and 200 mL of aq. 1N HCl wereadded. The organic layer was separated, and the aqueous layer wasextracted with CH₂Cl₂ (100 mL×2). The combined organic solution waswashed with brine, dried over anhydrous MgSO₄, filtered, andconcentrated under reduced pressure, to give acetate product as a whitesolid (25.4 g), which was used directly for the next step withoutfurther purification (Rege, P. D.; Tian, Y.; Corey, E. J. Org. Lett.2006, 8, 3117).

Fuming nitric acid (100 mL) was cooled to −15° C., and the acetate fromthe last step was carefully added in small portions. After addition, theresulting deep red solution was stirred for 3 h at −10-0° C., thenpoured into 400 mL of cold ice water and stirred for 20 min. The yellowsolid formed was filtered, thoroughly washed with cold water, and driedunder house vacuum overnight. The crude product (21.3 g) was directlyused for the next step without further purification.

The yellow solid from the previous step was added to 200 mL of aq. 2NKOH solution. The reaction mixture was heated to reflux for 10 min, andthen cooled to rt. A 50 mL of cold concentrated HCl was carefully addedto quench the reaction. The light yellow solid formed was filtered,thoroughly washed with cold water, and dried at rt. The crude productphenol (15.7 g) was obtained.

The light yellow solid from the last step was dissolved in 200 mL ofTHF. To this solution was added aq. NH₄OH (28-30%) (200 mL) and iodine(38 g). The dark mixture was stirred at rt for 24 h, then acidified withaq. 2N HCl until pH=7, and extracted with Et₂O (200 mL×3). The combinedorganic layer was washed with 10% Na₂S₂O₃ solution and brine, dried overanhydrous MgSO₄, filtered, and concentrated under vacuum. The crudeproduct obtained was further recrystallized in CH₂Cl₂ to give4-hydroxy-3-methoxy-2-nitrobenzonitrile as light yellow crystal (11.8 g)(Talukdar, S.; Hsu, J. L.; Chou, T. C.; Fang, J. M. Tetrahedron Lett.2001, 42, 1103).

To a mixture of NaH (3.0 g, 73.0 mmol) in 15 mL of DMF at 0° C., wasadded the solution of 4-hydroxy-3-methoxy-2-nitrobenzonitrile (11.8 g,60.8 mmol) in 15 mL of DMF. After 30 min, MeI (17.3 g, 121.6 mmol) wasadded dropwise. The mixture was stirred at rt for 2 h, and heated up to60° C. for 30 min. After cooled to rt, it was quenched with aq. 1N HCl.The reaction mixture was extracted with EtOAc (100 mL×3). The combinedorganic solution was washed with brine, dried over anhydrous MgSO₄,filtered, and concentrated under vacuum. The residue was purified byflash chromatography on silica gel (eluted with hexanes/EtOAc/CH2Cl₂;5:1:2, then 2:1:1), to give compound XS-3 as white solid (10.2 g, 37%yield over 5 steps).

3,4-dimethoxy-2-nitrobenzonitrile (XS-3)

m.p. 102-103° C.; ¹H NMR (500 MHz, CDCl₃) δ: 7.49 (d, J=8.5 Hz, 1H),7.08 (d, J=8.5 Hz, 1H), 4.00 (s, 3H), 3.98 (s, 3H); ¹³C NMR (125 MHz,CDCl₃) δ: 158.1, 142.5, 129.9, 114.5, 114.2, 98.0, 62.7, 57.0; HRMS(ESI) m/z: [M+Na]⁺ calcd for C₉H₈N₂NaO₄, 231.0382. found, 231.0379.

To a solution of XS-3 (2.47 g, 11.8 mmol) in anhydrous chlorobenzene (25mL) was added anhydrous ZnCl₂ (3.38 g, 24.8 mmol) and (R)-valinol (1.82g, 17.7 mmol) at rt. The solution was heated to reflux for 20 h beforequenched with water. The slurry was treated with ammonium hydroxide (20mL) with stirring for 30 min and extracted with EtOAc (20 mL×3). Thecombined organic layers were washed with brine, dried over anhydrousMg₂SO₄ and filtered. The solvent was removed under vacuum and theresidual was purified on silica gel by flash chromatography (eluted withhexanes/EtOAc (5:1 to 1:1)) to give product XS-4 (3.30 g, 95% yield) asa white solid.

(S)-2-(3,4-dimethoxy-2-nitrophenyl)-4-isopropyl-4,5-dihydrooxazole(XS-4)

[α]_(D) ²⁰=+64.0 (c 1.0, CHCl₃); m.p. 56-58° C.; ¹H NMR (500 MHz, CDCl₃)δ: 7.66 (d, J=8.5 Hz, 1H), 6.98 (d, J=8.5 Hz, 1H), 4.36-4.29 (m, 1H),4.12-4.02 (m, 2H), 3.94 (s, 3H), 3.91 (s, 3H), 1.85-1.74 (m, 1H), 0.97(d, J=6.5 Hz, 3H), 0.88 (d, J=6.5 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃) δ:158.6, 155.6, 140.9, 125.6, 112.7, 112.6, 72.7, 70.4, 62.2, 56.4, 32.7,18.6, 18.1; HRMS (ESI) m/z: [M+H]⁺ calcd for C₁₄H₁₉N₂O₅, 295.1294.found, 295.1291.

To a solution of XS-4 (3.30 g, 11.2 mmol) in EtOAc (22 mL) was addedPd/C (1.19 g, 10 mmol %). A hydrogen balloon was attached and thereaction was stirred for 3 h at rt. The slurry was filtered throughCelite pad and concentrated under vacuum. The residue was purified onsilica gel by flash chromatography (eluted with hexanes/EtOAc (10:1)) togive product XS-5 (2.43 g, 82%) as white solid.

(S)-6-(4-isopropyl-4,5-dihydrooxazol-2-yl)-2,3-dimethoxyaniline (XS-5)

[α]_(D) ²⁰=−26.4 (c 1.0, CHCl₃); m.p. 66-67° C.; ¹H NMR (500 MHz, CDCl₃)δ: 7.42 (d, J=8.5 Hz, 1H), 6.32 (br, 2H), 6.27 (d, J=8.5 Hz, 1H), 4.29(t, J=8.5 Hz, 1H), 4.07 (q, J=8.0 Hz, 1H), 3.97 (t, J=8.5 Hz, 1H), 3.87(s, 3H), 3.82 (s, 3H), 1.82-1.72 (m, 1H), 1.03 (d, J=7.0 Hz, 3H), 0.93(d, J=6.5 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃) δ: 163.3, 154.4, 143.4,134.5, 125.4, 104.1, 99.9, 72.9, 68.7, 59.6, 55.6, 33.2, 19.0, 18.6;HRMS (ESI) m/z: [M+H]⁺ calcd for C₁₄H₂₁N₂O₃, 265.1552. found, 265.1549.

To a solution of XS-5 (0.90 g, 3.4 mmol) in anhydrous pyridine (8 mL)was added 3,5-dichlorobenzenesulfonyl chloride (1.68 g, 6.8 mmol). Thesolution was stirred overnight at rt, then quenched with water (10 mL).The mixture was extracted with EtOAc (20 mL×3) and the combined organiclayers were washed with brine, dried over Na2SO4, and concentrated undervacuum. The residual was purified on silica gel by flash chromatography(eluted with hexanes/EtOAc (5:1)) to give pure product X-12 as a whitesolid (1.29 g, 80% yield). Recrystallization from hexanes gave whitecrystals.

(S)-3,5-dichloro-N-(6-(4-isopropyl-4,5-dihydrooxazol-2-yl)-2,3-dimethoxyphenyl)be-nzenesulfonamide(X-12)

[α]_(D) ²⁰=−16.2 (c 1.1, CHCl₃); m.p. 112-113° C.; ¹H NMR (500 MHz,CDCl₃) δ: 12.60 (br, 1H), 7.93 (s, 2H), 7.56 (d, J=9.0 Hz, 1H), 7.52 (s,1H), 6.70 (d, J=9.0 Hz, 1H), 4.41 (t, J=8.5 Hz, 1H), 4.17-4.07 (m, 2H),3.88 (s, 3H), 3.19 (s, 3H), 1.88-1.80 (m, 1H), 1.10 (d, J=7.0 Hz, 3H),1.00 (d, J=6.0 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃) δ: 163.2, 155.9, 145.4,140.9, 135.1, 133.4, 131.5, 125.2, 125.1, 110.4, 107.3, 72.4, 69.9,59.3, 55.9, 33.2, 18.7; HRMS (ESI) m/z: [M+Na]⁺ calcd forC₂₀H₂₂Cl₂N₂NaO₅S, 495.0524. found, 495.0533.

Synthesis of Trans-Bromoenone X-15-X-18 (FIG. 8)

Acetylenide Addition:

To a solution of trimethylsilyl acetylene (196.5 mg, 2.0 mmol) in THF(8.0 mL) was added dropwise n-butyllithium (2.5 M in hexanes, 0.72 mL,1.8 mmol) at −78° C. After 1 h, a solution of aldehyde XS-6 (1.0 mmol)in THF (2.0 mL) was added over 10 min. The resulting mixture was stirredat −78° C. for 2 h and then quenched with saturated NH₄Cl solution (10mL). The aqueous layer was extracted with EtOAc (10 mL×3) and hexanes(20 mL). The combined organic extracts were washed with brine (500 mL),dried over Na₂SO₄, and then passed through a pad of silica gel (10 g).Elution with hexanes/EtOAc (1:4, 50 mL) and concentration gave the crudeproduct XS-7, which was used for the next step without furtherpurification.

Direct Bromination:

To a solution of propargyl alcohol XS-7 (1.0 mmol) in acetone (10 mL)was added NBS (267 mg, 1.5 mmol) and silver nitrate AgNO₃ (17.2 mg, 0.1mmol) at rt. After 1 h, the reaction mixture was diluted with 10 mL Et₂Oand quenched by 10 mL 10% Na₂S₂O₃ solution. The aqueous layer wasextracted with Et₂O (10 mL×3) and the combined organic layer was washedwith 10% Na₂S₂O₃ solution (10 mL×2) and 20 mL brine. The organic layerwas dried over anhydrous MgSO₄ and concentrated under reduced pressure.The residue was passed through a silica gel pad (4:1 hexanes/EtOAc, 50mL) and the eluents was concentrated. The crude product XS-8 (a yellowliquid) was used for the next step without further purification.

DIBAL Reduction:

To a solution of aluminum trichloride AlCl₃ (166 mg, 2.0 mmol) in Et₂O(5 mL) was added slowly DIBAL solution (1.0M in THF, 4.0 mL, 4.0 mmol)at 0° C. The white solid was precipitated out from the reaction solutionwith addition of DIBAL solution. On the continuous addition of DIBALsolution, the white solid dissolved, and the solution became clearyellow or white precipitated yellow color. After the completion of DIBALaddition, the reaction mixture was stirred for 10-15 min. The solutionof propargyl alcohol XS-8 (˜1.0 mmol) in ethyl ether Et₂O (4.0+1.0 mL)was slowly added to the reaction mixture for ˜10 mins at 0° C. Thereaction mixture was warmed to room temperature and stirred for 1 h.With the completion of reaction (check TLC to make sure no SM left), thereaction mixture was cooled down to 0° C. and quenched slowly by MeOH(1.0 mL) (hydrogen gas release rapidly). To the reaction mixture wasadded the 20 mL saturated sodium potassium tartrate solution, and themixture was stirred vigorously overnight. The white aqueous layer wasextracted with EtOAc (3×10 mL) and the combined organic layer was washedwith 20 mL brine. The organic layer was dried over anhydrous MgSO₄ andconcentrated under reduced pressure. The residue was purified by columnchromatography on silica gel gave trans-allylic alcohol XS-9 as yellowoil.

Dess-Martin Oxidation:

trans-Allylic alcohol XS-9 was dissolved in wet CH₂Cl₂ (10 mL) at rt andthen DMP (636 mg, 1.5 mmol) and NaHCO₃ (840 mg, 10 mmol) were added tothe reaction solution. The reaction mixture was stirred for 1 h(monitored by TLC) and quenched by a mixture of 10% Na₂S₂O₃ solution(caution: cannot be saturated) (15 mL) and saturated NaHCO₃ solution (10mL). The solution was diluted with CH₂Cl₂ (10 mL) and stirred vigorouslyfor 15-30 min. The aqueous layer was extracted with CH₂Cl₂ (10 mL×4) andcombined organic layer was washed with 10% Na₂S₂O₃ solution twice (10mL), saturated aq. NaHCO₃ solution (10 mL) and brine (10 mL). Theorganic layer was dried over anhydrous MgSO₄ and concentrated underreduced pressure. The residue was purified by column chromatography onsilica gel to give the desired trans-bromoenone X-15-X-18.

(E)-1-bromo-5-((tert-butyldimethylsilyl)oxy)pent-1-en-3-one (X-15)

42% yield as a yellow oil; ¹H NMR (500 MHz, CDCl₃) δ: 7.56 (d, J=14.0Hz, 1H), 6.84 (d, J=14.5 Hz, 1H), 3.91 (t, J=6.0 Hz, 2H), 2.73 (t, J=6.5Hz, 2H), 0.87 (s, 9H), 0.04 (s, 6H); ¹³C NMR (125 MHz, CDCl₃) δ: 196.5,137.2, 126.6, 58.8, 43.8, 25.8, 18.2, −5.5; HRMS (ESI) m/z: [M+Na]⁺calcd for C₁₁H₂₁BrNaO₂Si, 315.0392. found, 315.0390.

(E)-1-bromo-5-phenylpent-1-en-3-one (X-16)

56% yield as a yellow oil; ¹H NMR (500 MHz, CDCl₃) δ: 7.53 (d, J=13.5Hz, 1H), 7.29 (t, J=7.5 Hz, 2H), 7.21 (d, J=7.5 Hz, 1H), 7.19 (d, J=7.5Hz, 2H), 6.80 (d, J=13.5 Hz, 1H), 2.98-2.92 (m, 2H), 2.88-2.83 (m, 2H);¹³C NMR (125 MHz, CDCl₃) δ: 196.2, 140.6, 136.4, 128.5, 128.3, 126.3,126.1, 42.5, 29.6; HRMS (ESI) m/z: [M+Na]⁺ calcd for C₁₁H₁₁BrNaO,260.9891. found, 260.9888.

(E)-1-bromo-5-(4-iodophenyl)pent-1-en-3-one (X-17)

62% yield as a yellow oil; ¹H NMR (500 MHz, CDCl₃) δ: 7.60 (d, J=8.0 Hz,2H), 7.53 (d, J=13.0 Hz, 1H), 6.93 (d, J=7.5 Hz, 2H), 7.79 (d, J=14.0Hz, 2H), 6.80 (d, J=13.5 Hz, 1H), 2.92-2.86 (m, 2H), 2.85-2.79 (m, 2H);¹³C NMR (125 MHz, CDCl₃) δ: 195.8, 140.2, 137.6, 136.2, 130.4, 126.4,91.4, 42.2, 28.9; HRMS (ESI) m/z: [M+H]⁺ calcd for C₁₁H₁₁BrIO, 364.9038.found, 364.9041.

(E)-1-bromo-5-(3-iodophenyl)pent-1-en-3-one (X-18)

63% yield as a yellow oil; ¹H NMR (500 MHz, CDCl₃) δ: 7.56 (d, J=14.0Hz, 1H), 7.57 (s, 2H), 7.17 (d, J=7.5 Hz, 1H), 7.04 (t, J=7.5 Hz, 1H),6.82 (d, J=14.0 Hz, 1H), 2.94-2.88 (m, 2H), 2.88-2.83 (m, 2H); ¹³C NMR(125 MHz, CDCl₃) δ: 195.6, 143.0, 137.3, 136.3, 135.4, 130.3, 127.7,126.4, 94.5, 42.2, 28.9; HRMS (ESI) nm/z: [M+H]⁺ calcd for C₁₁H₁₁BrIO,364.9038; found, 364.9032.

General Procedure (B) of Asymmetric Catalytic Ni/Cr-Mediated Couplingwith Trans Bromoenone X-14-X-18

To a mixture of natural sulfonamide X-12 (5.20 mg, 11.0 μmol), protonsponge (Aldrich, purified by sublimation; 2.36 mg, 11.0 μmol) and CrCl₂(Aldrich, 99.99% mg, 1.23 mg, 10.0 μmol) was added MeCN (Baker, ultralow water; 100 μL) in a glovebox. The mixture was stirred for 60 min atrt under nitrogen. To the second new vial were added Zr(cp)₂Cl₂(Aldrich, 98%; 43.8 mg, 0.15 mmol), Mn powder (Aldrich, 99.99%, powder;11.0 mg, 0.20 mmol), LiCl (Aldrich, anhydrous, grinded; 8.5 mg, 0.20mmol), NiCl₂ catalyst X-13b (0.033 mg, 0.05 μmol), aldehyde (32.7 mg,0.10 mmol), trans-bromoenone X-14-X-18 (0.15 mmol) and MeCN (Baker,ultra low water; 150 μL). The mixture in the first vial was transferredto the second vial with syringe under nitrogen. The reaction mixture wasstirred under nitrogen until the reaction was completed in about 3 h (byTLC), and diluted with EtOAc (2.0 mL). Florisil (ca. 50 mg) was added,and the mixture was stirred for 30 min, filtered through a short silicagel pad using EtOAc/hexanes (1:1). The eluent was concentrated in vacuoto furnish the crude coupling product. The crude product was purified bypreparative TLC (EtOAc/hexanes=1:4) to give X-11 to XS-21 as a yellowliquid.

(E)-1-((tert-butyldimethylsilyl)oxy)-2-hydroxydodec-3-en-5-one (XS-10)

84% yield; ¹H NMR (500 MHz, CDCl₃) δ: 6.73 (dd, J=15.5, 4.5 Hz, 1H),6.40 (dd, J=16.0, 2.0 Hz, 1H), 4.39-4.33 (m, 1H), 3.74 (dd, J=10.0, 4.0Hz, 1H), 3.49 (dd, J=10.0, 7.5 Hz, 1H), 2.70 (d, J=4.5 Hz, 1H), 2.53 (t,J=7.5 Hz, 2H), 1.64-1.56 (m, 2H), 1.33-1.21 (m, 8H), 0.90 (s, 9H), 0.87(t, J=7.0 Hz, 3H), 0.08 (s, 3H), 0.07 (s, 3H); 13C NMR (125 MHz, CDCl₃)δ: 200.4, 143.2, 129.5, 71.5, 66.2, 40.9, 31.6, 29.2, 29.0, 25.8, 24.1,22.6, 18.2, 14.0, −5.4, −5.5; HRMS (ESI) m/z: [M+Na]⁺ calcd forC₁₈H₃₆NaO₃Si, 351.2331. found, 351.2321.

(E)-1-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-1-hydroxyundec-2-en-4-one(XS-11)

86% yield; ¹H NMR (500 MHz, CDCl₃) δ: 6.75 (dd, J=16.0, 4.5 Hz, 1H),6.43 (dd, J=16.0, 1.5 Hz, 1H), 4.50-4.44 (m, 1H), 4.15 (q, J=6.0 Hz,1H), 3.94 (dd, J=8.5, 6.5 Hz, 1H), 3.87 (dd, J=8.5, 6.5 Hz, 1H), 2.53(t, J=7.5 Hz, 2H), 1.64-1.55 (m, 2H), 1.44 (s, 3H), 1.35 (s, 3H),1.32-1.19 (m, 8H), 0.86 (t, J=7.0 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃) δ:200.3, 142.1, 129.6, 109.8, 70.6, 64.7, 41.1, 31.6, 29.1, 29.0, 26.4,24.9, 24.0, 22.6, 14.0; HRMS (ESI) m/z: [M+Na]⁺ calcd for C₁₆H₂₈NaO₄,307.1885. found, 307.1879.

(E)-10-hydroxy-2,2,3,3,16,16-hexamethyl-15,15-diphenyl-4,14-dioxa-3,15-disilahept-adec-8-en-7-one(XS-12)

92% yield; ¹H NMR (500 MHz, CDCl₃) δ: 7.70-7.64 (m, 4H), 7.47-7.36 (m,6H), 6.82 (dd, J=16.0, 5.0 Hz, 1H), 6.36 (dd, J=16.0, 1.5 Hz, 1H),4.41-4.34 (m, 1H), 3.94 (t, J=6.5 Hz, 2H), 3.70 (d, J=5.5 Hz, 2H), 2.98(br, 1H), 2.79 (t, J=6.5 Hz, 2H), 1.86-1.77 (m, 1H), 1.74-1.61 (m, 3H),1.06 (s, 9H), 0.88 (s, 9H), 0.06 (s, 6H); ¹³C NMR (125 MHz, CDCl₃) δ:199.2, 148.4, 135.5, 133.2, 129.7, 128.6, 127.7, 70.8, 64.0, 59.0, 43.6,33.9, 28.3, 26.8, 26.7, 25.8, 19.1, 18.2; HRMS (ESI) m/z: [M+Na]⁺ calcdfor C₃₁H₄₈NaO₄Si₂, 563.2989. found, 563.2980.

(E)-9-((tert-butyldiphenylsilyl)oxy)-6-hydroxy-1-phenylnon-4-en-3-one(XS-13)

80% yield; ¹H NMR (500 MHz, CDCl₃) δ: 7.69-7.64 (m, 4H), 7.46-7.36 (m,6H), 7.31-7.26 (m, 2H), 7.22-7.17 (m, 3H), 6.80 (dd, J=16.0, 4.5 Hz,1H), 6.35 (dd, J=16.0, 2.0 Hz, 1H), 4.40-4.33 (m, 1H), 3.70 (t, J=5.5Hz, 2H), 2.96 (t, J=7.5 Hz, 2H), 2.89 (t, J=7.5 Hz, 2H), 1.84-1.76 (m,1H), 1.72-1.59 (m, 3H), 1.06 (s, 9H); ¹³C NMR (125 MHz, CDCl₃) δ: 199.4,148.2, 141.1, 135.5, 133.2, 129.8, 128.5, 128.4, 128.0, 127.7, 126.1,70.8, 64.1, 42.4, 34.0, 30.0, 28.3, 26.8, 19.1; HRMS (ESI) m/z: [M+Na]⁺calcd for C₃₁H₃₈NaO₃Si, 509.2488; found, 509.2479.

(E)-4-hydroxy-2-methyltetradeca-2,5-dien-7-one (XS-14)

82% yield; ¹H NMR (500 MHz, CDCl₃) δ: 6.73 (dd, J=16.0, 5.0 Hz, 1H),6.28 (dd, J=16.0, 2.0 Hz, 1H), 5.15 (dt, J=9.0, 1.5 Hz, 1H), 5.08-5.01(m, 1H), 2.55 (t, J=7.5 Hz, 2H), 1.76 (d, J=1.0 Hz, 3H), 1.74 (d, J=1.0Hz, 3H), 1.63-1.58 (m, 2H), 1.35-1.20 (m, 8H), 0.88 (t, J=7.0 Hz, 3H);¹³C NMR (125 MHz, CDCl₃) δ: 201.0, 146.2, 137.4, 127.7, 124.3, 68.4,40.6, 31.7, 29.2, 29.1, 25.8, 24.1, 22.6, 18.4, 14.0; HRMS (ESI) m/z:[M+Na]⁺ calcd for C₁₅H₂₆NaO₂, 261.1830; found, 261.1835.

(E)-1-hydroxy-1-phenylundec-2-en-4-one (XS-15)

83% yield; ¹H NMR (500 MHz, CDCl₃) δ: 7.42-7.30 (m, 5H), 6.88 (dd,J=15.5, 4.5 Hz, 1H), 6.42 (dd, J=16.0, 1.5 Hz, 1H), 5.38 (d, J=4.0 Hz,1H), 2.56 (t, J=7.5 Hz, 2H), 2.15 (br, 1H), 1.66-1.54 (m, 4H), 1.36-1.18(m, 6H), 0.87 (t, J=7.0 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃) δ: 200.8,146.0, 141.0, 128.9, 128.4, 128.1, 126.5, 73.8, 40.8, 31.7, 29.2, 29.1,24.1, 22.6, 14.0; HRMS (ESI) m/z: [M+H]⁺ calcd for C₁₇H₂₅O₂, 261.1855.found, 261.1873.

(E)-1-cyclohexyl-1-hydroxyundec-2-en-4-one (XS-16)

91% yield; ¹H NMR (500 MHz, CDCl₃) δ: 6.80 (dd, J=16.0, 5.0 Hz, 1H),6.29 (dd, J=16.0, 1.5 Hz, 1H), 4.09 (q, J=5.0 Hz, 1H), 2.55 (t, J=7.5Hz, 2H), 1.82-1.72 (m, 3H), 1.71-1.65 (m, 2H), 1.64-1.59 (m, 2H),1.55-1.47 (m, 1H), 1.33-1.24 (m, 8H), 1.24-1.00 (m, 6H), 0.88 (t, J=7.0Hz, 3H); ¹³C NMR (125 MHz, CDCl₃) δ: 200.4, 143.2, 129.5, 71.5, 66.2,40.9, 31.6, 29.2, 29.0, 25.8, 24.1, 22.6, 18.2, 14.0, −5.4, −5.5; HRMS(EST) n/z: [M+H]⁺ calcd for C₁₇H₃₁O₂, 267.2324; found, 267.2333.

(E)-1-(furan-2-yl)-1-hydroxyundec-2-en-4-one (XS-17)

83% yield; ¹H NMR (500 MHz, CDCl₃) δ: 7.41 (d, J=1.5 Hz, 1H), 6.94 (dd,J=16.0, 5.0 Hz, 1H), 6.46 (dd, J=16.0, 2.0 Hz, 1H), 6.35 (dd, J=3.0, 1.5Hz, 1H), 6.28 (d, J=3.0 Hz, 1H), 5.41 (s, 1H), 2.58 (t, J=7.5 Hz, 2H),2.40 (br, 1H), 1.65-1.56 (m, 2H), 1.36-1.16 (m, 8H), 0.87 (t, J=7.0 Hz,3H); ¹³C NMR (125 MHz, CDCl₃) δ: 200.5, 153.2, 142.9, 142.5, 129.4,110.5, 107.6, 67.0, 41.0, 31.6, 29.2, 29.0, 24.0, 22.6, 14.0; HRMS (ESI)m/z: [M+Na]⁺ calcd for C₁₅H₂₂NaO₃, 273.1467. found, 273.1473.

(E)-6-hydroxy-1,6-diphenylhex-4-en-3-one (XS-18)

83% yield; H NMR (500 MHz, CDCl₃) δ: 7.39-7.35 (m, 2H), 7.34-7.30 (m,3H), 7.29-7.24 (m, 2H), 7.21-7.16 (m, 3H), 6.87 (dd, J=13.5, 3.5 Hz,1H), 6.41 (dd, J=13.5, 1.5 Hz, 1H), 5.35 (s, 1H), 2.95-2.87 (m, 4H),2.38 (d, J=3.0 Hz, 1H); ¹³C NMR (125 MHz, CDCl₃) δ: 199.5, 146.5, 141.0,140.9, 128.9, 128.5, 128.4, 128.3, 127.9, 126.5, 126.1, 73.7, 42.2,29.8; HRMS (EST) m/z: [M+Na]+ calcd for C₁₈H₁₈NaO₂, 289.1204. found,289.1208.

(E)-6-(furan-2-yl)-6-hydroxy-1-phenylhex-4-en-3-one (XS-19)

90% yield; ¹H NMR (500 MHz, CDCl₃) δ: 7.42 (d, J=7.5 Hz, 1H), 7.30 (d,J=7.5 Hz, 2H), 7.24-7.18 (m, 3H), 6.95 (dd, J=16.0, 4.5 Hz, 1H), 6.48(dd, J=16.0, 2.0 Hz, 1H), 6.37 (dd, J=3.5, 2.0 Hz, 1H), 6.28 (d, J=3.5Hz, 1H), 6.41 (t, J=3.5 Hz, 1H), 3.01-2.88 (m, 4H), 2.46 (d, J=5.0 Hz,1H); ¹³C NMR (125 MHz, CDCl₃) δ: 199.2, 153.1, 143.1, 142.9, 141.0,129.3, 128.5, 128.3, 126.1, 110.5, 107.6, 66.9, 42.4, 29.8; HRMS (ESI)m/z: [M+Na]⁺ calcd for C₁₆H₁₆NaO₃, 279.0997. found, 279.1005.

(E)-9-((tert-butyldiphenylsilyl)oxy)-6-hydroxy-1-(4-iodophenyl)non-4-en-3-one(XS-20)

82% yield; ¹H NMR (500 MHz, CDCl₃) δ: 7.68-7.64 (m, 4H), 7.59 (d, J=8.5Hz, 2H), 7.44-7.36 (m, 6H), 6.95 (d, J=8.0 Hz, 2H), 6.79 (dd, J=16.0,4.5 Hz, 1H), 6.35 (dd, J=16.0, 2.0 Hz, 1H), 4.38-4.33 (m, 1H), 3.70 (t,J=5.0 Hz, 2H), 3.00 (d, J=4.5 Hz, 1H), 2.91-2.83 (m, 4H), 1.82-1.77 (m,1H), 1.71-1.62 (m, 2H), 1.06 (s, 9H); ¹³C NMR (125 MHz, CDCl₃) δ: 198.9,148.3, 140.8, 137.5, 135.5, 133.2, 130.5, 129.8, 127.9, 127.7, 91.1,70.8, 64.1, 42.0, 34.1, 29.3, 28.3, 26.8, 19.1; HRMS (ESI) m/z: [M+Na]⁺calcd for C₃₁H₃₇INaO₃Si, 635.1454. found, 635.1450.

(E)-9-((tert-butyldiphenylsilyl)oxy)-6-hydroxy-1-(3-iodophenyl)non-4-en-3-one(XS-21)

87% yield; ¹H NMR (500 MHz, CDCl₃) δ: 7.67-7.64 (m, 4H), 7.56 (s, 1H),7.53 (d, J=7.5 Hz, 1H), 7.46-7.41 (m, 2H), 7.40-7.37 (m, 4H), 7.16 (d,J=8.0 Hz, 1H), 7.01 (t, J=8.0 Hz, 1H), 6.80 (dd, J=16.0, 4.5 Hz, 1H),6.35 (dd, J=16.0, 1.5 Hz, 1H), 4.40-4.34 (m, 1H), 3.70 (t, J=5.5 Hz,2H), 3.00 (d, J=4.0 Hz, 1H), 2.92-2.83 (m, 4H), 1.84-1.77 (m, 1H),1.71-1.62 (m, 2H), 1.06 (s, 9H); ¹³C NMR (125 MHz, CDCl₃) δ: 198.8,148.4, 143.6, 137.4, 135.5, 135.5, 135.2, 133.2, 130.2, 129.8, 127.9,127.7, 94.5, 70.8, 64.1, 42.0, 34.1, 29.3, 28.3, 26.8, 19.1; HRMS (ESI)m/z: [M+Na]⁺ calcd for C₃₁H₃₇INaO₃Si, 635.1454. found, 635.1446.

Synthesis Outlined in FIG. 9 Synthesis of Cis-Bromoenone X-19

To a solution of 1-decyn-3-one XS-2 (0.26 g, 1.7 mmol) in acetic acid(AcOH, 3.4 mL) was added LiBr (174.0 mg, 2.0 mmol). The reaction mixturewas stirred overnight, and then diluted with 20 mL H₂O. The aqueoussolution was extracted with Et₂O (20 mL×3) and combined organic extractswere washed with saturated aq. NaHCO₃ solution (20 mL×2) and 20 mL ofbrine. The organic layer was dried over anhydrous MgSO₄ and concentratedunder reduced pressure. The residue was purified by flash columnchromatography on silica gel with eluent of hexanes/Et₂O (100:1). The(Z)-1-bromodec-1-en-3-one X-19 was obtained as light yellow oil (70%yield). ¹H NMR (500 MHz, C₆D₆) δ: 6.16 (d, J=8.5 Hz, 1H), 6.05 (d, J=8.5Hz, 1H), 2.18 (t, J=7.5 Hz, 2H), 1.49 (quint, J=7.5 Hz, 2H), 1.30-1.20(m, 2H), 1.20-1.09 (m, 6H), 0.88 (t, J=7.5 Hz, 3H); ¹³C NMR (125 MHz,C₆D₆) δ: 197.6, 131.6, 115.5, 43.9, 32.0, 29.4, 29.3, 24.0, 22.9, 14.3;HRMS (ESI) m/z: [M+H]⁺ calcd for C₁₀H₁₈BrO, 233.0541. found, 233.0544.

Asymmetric Catalytic Ni/Cr-Mediated Coupling with Cis-Bromoenone X-19

The procedure was the same as procedure B. The products were obtained asa mixture of furan X-20 and X-11 (80% yield, 1:9) (Sammond, D. M.;Sammakia, T. Tetrahedron Lett. 1996, 37, 6065).

tert-butyl(3-(5-heptylfuran-2-yl)propoxy)diphenylsilane (X-20)

8% yield; 1H NMR (500 MHz, CDCl₃) δ: 7.70-7.64 (m, 4H), 7.45-7.35 (m,6H), 5.83 (d, J=3.0 Hz, 1H), 5.82 (d, J=3.0 Hz, 1H), 3.71 (t, J=6.0 Hz,2H), 2.71 (t, J=7.5 Hz, 2H), 2.55 (t, J=7.5 Hz, 2H), 1.89 (quint, J=6.5Hz, 2H), 1.64-1.54 (m, 4H), 1.38-1.19 (m, 8H), 1.06 (s, 9H), 0.88 (t,J=7.0 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃) δ: 154.8, 154.0 135.6, 134.0,129.5, 127.6, 105.1, 104.8, 63.1, 31.8, 31.0, 29.2, 29.0, 28.1, 28.0,26.8, 24.4, 22.6, 19.2, 14.1; HRMS (ESI) m/z: [M+H]⁺ calcd forC₃₀H₄₃O₂Si, 463.3032. found, 463.3030.

Acid Catalyzed Formation of Furan from Corresponding Trans-CouplingProduct

The trans-coupling product (20 μmol) was dissolved in MeCN (0.5 mL)containing p-toluenesulfonic acid (p-TSA, 0.69 mg, 4 μmol) and thereaction mixture was stirred at rt for 2 h. The reaction was quenchedwith solid NaHCO₃ (3.36 mg, 40 μmol) and passed through a short silicagel pad with Hex/EtOAc (10:1). On removal of solvent, the furan productwas obtained as yellow oil.

tert-butyl(3-(5-(2-((tert-butyldimethylsilyl)oxy)ethyl)furan-2-yl)propoxy)diphenylsil-ane(XS-22)

86% yield; ¹H NMR (500 MHz, CDCl₃) δ: 7.70-7.66 (m, 4H), 7.45-7.40 (m,2H), 7.39-7.36 (m, 4H), 5.92 (d, J=3.0 Hz, 1H), 5.84 (d, J=3.5 Hz, 1H),3.83 (t, J=6.5 Hz, 2H), 3.72 (t, J=6.5 Hz, 2H), 2.80 (t, J=7.0 Hz, 2H),2.71 (t, J=7.5 Hz, 2H), 1.89 (quint, J=6.5 Hz, 2H), 1.07 (s, 9H), 0.89(s, 9H), 0.02 (s, 6H); ¹³C NMR (125 MHz, CDCl₃) δ: 154.3, 151.3, 135.6,134.0, 129.5, 127.6, 106.5, 105.3, 63.1, 61.9, 32.0, 30.9, 26.8, 26.0,24.4, 19.2, 18.3, −5.4; HRMS (ESI) m/z: [M+Na]⁺ calcd for C₃₁H₄₆NaO₃Si₂,545.2883. found, 545.2879.

Synthesis of Tri-Substituted Bromoenone X-21-X-22.

For the preparation of undec-2-yn-4-one, refer to the proceeding paper(Wender, P. A.; Bi, F. C.; Brodney, M. A.; Gosselin, F. Org. Lett. 2001,3, 2105).

To a solution of undec-2-yn-4-one (0.33 g, 2 mmol) in trifluoroaceticacid (TFA, 4.0 mL) was added LiBr (208 mg, 2.4 mmol). The reactionmixture was stirred for 1 h, and then poured in 20 mL saturated aq.NaHCO₃ solution. NaHCO₃ (solid) was added in small portions, and thesolution was vigorously stirred until the pH of the reaction mixturebecame neutral. The reaction mixture was extracted with Et₂O (30 mL×3)and combined organic extracts were washed with 50 mL of saturated NaHCO₃solution and 30 mL of brine. The organic layer was dried over anhydrousMgSO₄ and concentrated under reduced pressure to give a residue, whichwas separated by preparative TLC (hexanes/EtOAc=4:1), to give E-isomerX-21 and Z-isomer X-22 as light yellow oils in 30% and 24% yields,respectively.

(E)-2-bromoundec-2-en-4-one (X-21)

30% yield; ¹H NMR (500 MHz, CDCl₃) δ: 6.69 (s, 1H), 2.75 (s, 3H), 2.41(t, J=7.5 Hz, 2H), 1.64-1.53 (m, 2H), 1.35-1.21 (m, 10H), 0.91-0.82 (m,3H); ¹³C NMR (125 MHz, CDCl₃) δ: 198.5, 143.2, 129.9, 44.5, 31.6, 29.1,29.0, 26.8, 24.0, 22.6, 14.0; HRMS (ESI) m/z: [M+H]⁺ calcd forC₁₁H₂₀BrO, 247.0698. found, 247.0702.

(Z)-2-bromoundec-2-en-4-one (X-22)

24% yield; ¹H NMR (500 MHz, CDCl₃) δ: 6.56 (s, 1H), 2.53 (t, J=7.5 Hz,2H), 2.44 (s, 3H), 1.64-1.55 (m, 2H), 1.35-1.21 (m, 10H), 0.91-0.82 (m,3H); ¹³C NMR (125 MHz, CDCl₃) δ: 198.8, 132.3, 127.1, 44.0, 31.7, 31.1,29.1, 29.0, 23.8, 22.6, 14.0; HRMS (ESI) m/z: [M+H]⁺ calcd forC₁₁H₂₀BrO, 247.0698; found, 247.0690.

Asymmetric Catalytic Ni/Cr-Mediated Coupling with Tri-SubstitutedBromoenone

The procedure was similar to procedure A. The NiCl₂ catalyst was X-13bwith 1.0 mol % loading. By preparative TLC (20% EtOAc in hexanes),alcohol X-23 and furan X-24 were isolated.

(E)-1-((tert-butyldiphenylsilyl)oxy)-4-hydroxy-5-methyltetradec-5-en-7-one(X-23)

¹H NMR (500 MHz, CDCl₃) δ: 7.69-7.64 (m, 4H), 7.46-7.35 (m, 6H), 6.36(s, 1H), 4.10 (t, J=7.0 Hz, 1H), 3.69 (t, J=5.5 Hz, 2H), 2.44 (t, J=7.0Hz, 2H), 2.08 (s, 3H), 1.83 (quin, J=7.5 Hz, 2H), 1.60-1.52 (m, 4H),1.38-1.20 (m, 8H), 1.06 (s, 9H), 0.87 (t, J=7.0 Hz, 3H); ¹³C NMR (125MHz, CDCl₃) δ: 202.0, 158.0, 135.5, 133.3, 129.8, 127.7, 121.7, 76.0,64.1, 44.7, 32.4, 31.7, 29.3, 29.1, 28.3, 26.8, 24.2, 22.6, 19.1, 15.8,14.1; HRMS (ESI) m/z: [M+Na]⁺ calcd for C₃₁H₄₆NaO₃Si, 517.3114. found,517.3120.

tert-butyl(3-(5-heptyl-3-methylfuran-2-yl)propoxy)diphenylsilane (X-24)

¹H NMR (500 MHz, CDCl₃) δ: 7.69-7.64 (m, 4H), 7.44-7.34 (m, 6H), 5.73(s, 1H), 3.67 (t, J=6.0 Hz, 2H), 2.63 (t, J=7.5 Hz, 2H), 2.50 (t, J=7.5Hz, 2H), 1.89 (s, 3H), 1.83 (quin, J=7.5 Hz, 2H), 1.60-1.52 (m, 4H),1.38-1.20 (m, 8H), 1.06 (s, 9H), 0.87 (t, J=7.0 Hz, 3H); ¹³C NMR (125MHz, CDCl₃) δ: 153.7, 148.7, 135.6, 134.0, 129.5, 127.6, 114.1, 107.6,63.1, 31.8, 31.6, 29.2, 29.0, 28.1, 28.0, 26.9, 22.6, 22.1, 19.2, 14.1,9.9. HRMS (ESI) m/z: [M+H]⁺ calcd for C₃₁H₄₅O₂Si, 477.3189. found,477.3194.

Synthesis Outlined in FIG. 11

Competition Studies of Ni/Cr-Mediated Coupling Reactions withTrans-Bromoenone and Alkenyl Iodides X-31a-c

Preparation of Chromium Sulfonamide Solution:

In a glove box, to a 5.0 mL black cap vial, was added chiral sulfonamideX-12 (52.0 mg, 0.11 mmol), proton sponge (Aldrich, purified bysublimation; 23.6 mg, 0.11 mmol) and CrCl₂(Aldrich, 99.99% mg, 12.3 mg,0.1 mmol), and MeCN (Baker, ultra low water; 1.0 mL). The mixture wasstirred for 60 min at rt under nitrogen and changed to deep greenhomogeneous solution which is ready to use for coupling reaction.

To a second 1.0 mL black cap vial were added aldehyde X-10 (16.4 mg,0.05 mmol), bromoenone X-9b (17.5 mg, 0.075 mmol), vinyl iodide X-31a-c(15.8 mg, 0.075 mmol), LiCl (Aldrich, anhydrous, grinded; 4.3 mg, 0.1mmol), Mn powder (Aldrich, 99.99%, powder; 5.5 mg, 0.1 mmol), Zr(Cp)₂Cl₂(Aldrich, 98%; 21.9 mg, 0.075 mmol), NiCl₂ catalyst X-13a or X-13b(x=0.05 mol %, 0.1 mol %, 0.5 mol % or 1.0 mol %) and MeCN (Baker, ultralow water; 75 ML). The green solution of chromium catalyst (50 μL) fromthe first vial was transferred to the second vial with microlitersyringe. The reaction mixture was stirred under nitrogen for 3 h, anddiluted with EtOAc (1.0 mL). Florisil (ca. 30 mg) was added, and themixture was stirred for 30 min, filtered through a short silica gel padtwice using hexanes/EtOAc (1:1) The eluent was concentrated in vacuo tofurnish the crude coupling product. The ratio analysis of crude couplingproducts X-32a-c was done with ¹H NMR.

1-((tert-butyldiphenylsilyl)oxy)-5-methylenenonan-4-ol (X-32a)

Clear oil; ¹H NMR (600 MHz, CDCl₃) δ: 7.69-7.67 (m, 4H), 7.45-7.38 (m,6H), 5.04 (s, 1H), 4.86 (s, 1H), 4.13-4.10 (m, 1H), 3.73-3.67 (m, 2H),2.12-2.06 (m, 1H), 2.02 (d, J=3.6 Hz, 1H), 2.02-1.96 (m, 1H), 1.80-1.72(m, 1H), 1.70-1.60 (m, 3H), 1.50-1.45 (m, 2H), 1.41-1.32 (m, 2H), 1.07(s, 9H), 0.93 (t, J=7.2 Hz, 3H); ¹³C NMR (150 MHz, CDCl₃) δ: 152.1,135.6, 134.8, 133.7, 129.6, 127.6, 109.1, 75.0, 63.9, 32.3, 31.3, 30.2,28.6, 26.8, 22.7, 19.2, 14.0; HRMS (ESI) m/z: [M+Na]⁺ calcd forC₂₆H₃₈NaO₂Si, 433.2539. found, 433.2541.

(E)-1-((tert-butyldiphenylsilyl)oxy)dec-5-en-4-ol (X-32b)

Clear oil; ¹H NMR (600 MHz, CDCl₃) δ: 7.69-7.67 (m, 4H), 7.45-7.38 (m,6H), 5.64 (dt, J=15.0, 7.2 Hz, 1H), 5.46 (dd, J=15.0, 7.2 Hz, 1H), 4.08(m, 1H), 3.69 (t, J=6.0 Hz, 2H), 2.04 (q, J=7.2 Hz, 2H), 1.92 (d, J=3.6Hz, 1H), 1.66-1.62 (m, 4H), 1.40-1.30 (m, 4H), 1.05 (s, 9H), 0.91 (t,J=6.6 Hz, 3H); ¹³C NMR (150 MHz, CDCl₃) δ: 135.5, 133.8, 132.9, 132.0,129.6, 127.6, 72.8, 64.0, 34.1, 31.8, 31.3, 28.6, 26.8, 22.2, 19.2,13.9; HRMS (ESI) m/z: [M+Na]⁺ calcd for C₂₆H₃₈NaO₂Si, 433.2539. found,433.2532.

(Z)-1-((tert-butyldiphenylsilyl)oxy)dec-5-en-4-ol (X-32c)

Clear oil; ¹H NMR (600 MHz, CDCl₃) δ: 7.69-7.67 (m, 4H), 7.45-7.38 (m,6H), 5.51-5.47 (m, 1H), 5.41-5.38 (m, 1H), 4.47 (m, 1H), 3.73-3.67 (m,2H), 2.13-2.03 (m, 2H), 1.88 (d, J=3.6 Hz, 1H), 1.72-1.57 (m, 4H),1.39-1.30 (m, 4H), 1.06 (s, 9H), 0.91 (t, J=7.2 Hz, 3H); ¹³C NMR (150MHz, CDCl₃) δ: 135.5, 133.7, 132.5, 132.1, 129.6, 127.6, 67.5, 63.9,34.3, 31.8, 28.5, 27.4, 26.8, 22.3, 19.2, 13.9; HRMS (ESI) m/z: [M+Na]⁺calcd for C₂₆H₃₈NaO₂Si, 433.2539. found, 433.2529.

TABLE 1 Results loading X-11:X-32a X-11:X-32b X-11:X-32c (mol %) X-13aX-13b X-13a X-13b X-13a X-13b 0.05 >100:1 >100:1  38:1  71:1 >100:1  >100:1 0.1 >100:1 >100:1  30:1   36:1 42:1 >100:1 0.5  38:166:1 1:1.1 12:1 16:1  46:1 1  22:1 26:1 1:2.3 1.5:1  4.6:1   5.2:1 2   6:1 11:1 1:13  0.7:1    1:1.8  1.2:1

Synthesis Outlined in FIG. 12 Synthesis of C14-C19 Building Block XS-27

A 1000 mL round-bottom flask was charged with penten-1-ol (TCI, 51.8 g,0.6 mol, 1.0 equiv) and dissolved in CH₂Cl₂ (500 mL, 1.2 M). Thereaction was then added sequentially with tert-butyldimethylsilylchloride (99.5 g, 0.66 mol, 1.1 equiv) and imidazole (49.0 g, 0.72 mol,1.2 equiv), and allowed to stir at rt for 2 h. The reaction slurry wasthen washed with saturated NaCl solution (200 mL twice). The aqueousphase was extracted with CH2Cl₂ (100 mL twice) and the combined organiclayer was dried over anhydrous MgSO₄. The solvent was removed underreduced pressure to afford a crude product, which was purified by housevacuum distillation at 105° C. to afford the producttert-butyldimethyl(pent-4-en-1-yloxy)silane as a clear oil (119.3 g, 99%yield).

A solution of oxone (246.0 g, 0.40 mol) in water (1000 mL) was addeddropwise at 0° C. to a vigorously stirred biphasic mixture oftert-butyldimethyl(pent-4-en-1-yloxy)silane (40.0 g, 0.4 mol),tetrabutylammonium hydrogen sulfate (22.6 g, 66.6 mmol), acetone (84mL), CH₂Cl₂ (840 mL) and a saturated NaHCO₃ solution (1400 mL) (Lafont,D.; D'Attoma, J.; Gomez, R.; Goekjian, P. G. Tetrahedron: Asymmetry2011, 22, 1197). With stirring, the mixture was maintained for 30 min at0° C., and 40 h at room temperature. The aqueous phase was extractedwith CH₂Cl₂ (400 mL twice) and the combined organic phases were washedwith saturated Na₂S₂O₃ solution (400 mL twice), saturated NaHCO₃solution (600 mL) and brine (400 mL twice) and dried over anhydrousMgSO₄. After filtration, the solution was concentrated under reducedpressure and the residue was purified by column chromatography to removeunreacted starting materials (about 10%), and the racemic epoxide XS-23was obtained as a light yellow oil (38.0 g, 88% yield).

Catalyst Activation for Jacobsen Kinetic Resolution

(Tokunaga, M.; Larrow, J. F.; Kakiuchi, F.; Jacobsen, E. N. Science1997, 277, 936): a mixture of (S,S)-Jacobsen catalyst (604 mg, 1 mmol),toluene (11 mL), and acetic acid (120 mg, 2 mmol, 2 equivalents tocatalyst) was stirred while open to the air for 2 h at room temperature.The solvent was removed by rotary evaporation, and the deep brownresidue was dried under vacuum overnight.

The solution of racemic epoxide XS-23 (48 g, 0.22 mol) in tert-BuOMe (50mL) and water (2.0 g, 0.11 mol) were added to the activated catalystflask, and then the reaction mixture was stirred at room temperature for6 h (¹H NMR indicated about 67% conversion). The reaction solvent wasremoved by reduced pressure and the residue was purified by columnchromatography to yield (S)-epoxide product XS-24 (yellow oil, 20.8 g,43% yield) and crude (R)-diol (23.4 g, 48% yield).

To a solution of trimethylsilyl acetylene (12.0 g, 122.2 mmol) in THF(150 mL) was added slowly n-butyllithium (1.6 M in hexanes, 76.4 mL,122.2 mmol) at −78° C. After 1.5 h, a solution of boron trifluorideetherate BF₃.Et₂O (16.8 mL, 135.8 mmol) in THF (30 mL) was added over 30min and the mixture was stirred for another 1 h. A solution of chiralepoxide XS-24 (14.7 g, 67.9 mmol) in THF (30 mL) was added over 30 min.The resulting mixture was stirred at −78° C. for 2 h and then directlypoured into a saturated aq. NaHCO₃ solution (500 mL) and extracted withEtOAc (500 mL×3) and hexanes (500 mL). The extracts were washed withbrine (500 mL), dried over Na2SO₄, passed through a pad of silica gel(60 g), and eluted with hexanes/EtOAc (1:4, 500 mL). The eluent wasconcentration under reduced pressure, to give the crude product (19.6g), which was used for the next step without further purification.

The crude product (19.6 g, 62.3 mmol) was dissolved in anhydrousmethanol (200 mL). To the solution, anhydrous K₂CO₃ (17.2 g, 124.6 mmol)was added in one portion and the reaction mixture was stirred at rt for4 h. The mixture was filtrated to remove excess amount of K₂CO₃ solidsand quenched by saturated NaHCO₃ solution (300 mL) and extracted withEtOAc (300 mL×3) and hexanes (300 mL). The combined extracts were washedwith brine (400 mL) and dried over Na₂SO₄. Concentration of the extractsunder reduced pressure gave a residue, which was purified by columnchromatography (100 g of silica gel). The homopropargylic alcohol XS-25was obtained as a yellow liquid (14.2 g, 86.5% in two steps). Theoptical purity of alcohol XS-25 was determined as >99% ee by ¹H NMR (500MHz) analysis of its (S)-(+)-Mosher ester.

(S)-7-((tert-butyldimethylsilyl)oxy)hept-1-yn-4-ol (XS-25)

[α]_(D) ²⁰=−11.0 (c 0.1, CH₂Cl₂); ¹H NMR (500 MHz, CDCl₃) δ: 3.81-3.75(m, 1H), 3.72-3.63 (m, 2H), 2.40-2.38 (m, 2H), 2.03 (t, J=2.5 Hz, 1H),1.82-1.74 (m, 1H), 1.73-1.63 (m, 2H), 1.62-1.54 (m, 1H), 0.89 (s, 9H),0.07 (s, 6H); ¹³C NMR (125 MHz, CDCl₃) □□ 81.2, 70.4, 69.8, 63.4, 33.6,29.1, 27.2, 25.9, 18.3, −5.4; HRMS (ESI) m/z: [M+H]⁺ calcd forC₁₃H₂₇O₂Si, 243.1780; found, 243.1787.

To a solution of homopropargylic alcohol XS-25 (7.3 g, 30.0 mmol) inCH₂Cl₂ (150 mL) was added pyridine (7.1 g, 90 mmol), triphenylphosphine(PPh₃, 11.8 g, 45 mmol) and trichloroacetamide (7.3 g, 45 mmol) at rt.The reaction was stirred at rt for 20 h under N₂, and then washed withbrine (60 mL×3). The organic layer was dried over Na₂SO₄ andconcentrated under reduced pressure. The residue was passed through asilica gel pad (50 g) with hexanes/EtOAc (30:1, 600 mL), to givehomopropargylic chloride XS-26 (7.2 g, 92.0%) as a light yellow oil.

(R)-tert-butyl((4-chlorohept-6-yn-1-yl)oxy)dimethylsilane (XS-26)

[α]_(D) ²⁰=+30.0 (c 0.1, CH₂Cl₂); ¹H NMR (500 MHz, CDCl₃) δ: 4.06-4.00(m, 1H), 3.68-3.62 (m, 2H), 2.73-2.62 (m, 2H), 2.09 (t, J=2.5 Hz, 1H),2.08-2.01 (m, 1H), 1.83-1.72 (m, 2H), 1.69-1.59 (m, 1H), 0.89 (s, 9H),0.05 (s, 6H); ¹³C NMR (125 MHz, CDCl₃) δ: 79.9, 70.9, 62.3, 59.8, 33.7,29.5, 28.6, 25.9, 18.3, −5.3; HRMS (ESI) m/z: [M+H]⁺ calcd forC₁₃H₂₆ClOSi, 261.1441; found, 261.1438.

To a solution of alkyne XS-26 (20.8 g, 80 mmol) in CH₂Cl₂ (400 mL) wasdropped B-iodo-9-BBN (Liu, S.; Kim, J. T.; Dong, C. G.; Kishi, Y. Org.Lett. 2009, 11, 4520) solution (1 M in CH₂Cl₂, 96 mL, 96 mmol) at 0° C.and stirred for 4 h at the same temperature prior to the addition ofAcOH (18.2 mL, 320 mmol). After stirring at 0° C. for 60 min, thereaction mixture was titrated with 30% aqueous H₂O₂ solution (red color)and then with slow addition of aqueous Na₂S₂O₃ (colorless) (caution:this process released tremendous heat). The aqueous phase was extractedwith CH₂Cl₂ three times and the combined organic extracts were washedwith 10 wt. % Na₂S₂O₃ and saturated NaHCO₃ solution, dried overanhydrous MgSO₄, and concentrated under vacuum. The residue was purifiedby flash column chromatography on silica gel eluted with hexanes/EtOAc(10:1 to 2:1) to give alcohol XS-27 (18.8 g, 86%) as a light yellowliquid.

(R)-4-chloro-6-iodohept-6-en-1-ol (XS-27)

[α]_(D) ²⁰=+1.2 (c 1.00, CHCl₃); ¹H NMR (500 MHz, C₆D₆) δ: 5.73 (d,J=1.0 Hz, 1H), 5.58 (d, J=1.0 Hz, 1H), 4.08-4.00 (m, 1H), 3.20 (t, J=5.5Hz, 2H), 2.42 (dd, J=14.5, 8.0 Hz, 1H), 2.35 (dd, J=14.5, 5.5 Hz, 1H),1.57-1.48 (m, 2H), 1.47-1.40 (m, 1H), 1.38-1.28 (1H, m); ¹³C NMR (125MHz, C₆D₆) δ: 128.7, 106.7, 61.8, 61.2, 53.5, 33.9, 29.6; HRMS (ESI)m/z: [M+Na]⁺ calcd for C₇H₁₂OIClNa, 296.9519. found, 296.9513.

The optical purity of alcohol XS-27 was determined as >99% ee by HPLCanalysis (OJ-H chiral column) of its 4-acetylphenylurethane derivativeXS-28 prepared from XS-27.

To a solution of alcohol XS-27 (51 mg, 0.2 mmol) in CH₂Cl₂ (1.0 mL) wereadded 4-acetylphenyl isocyanate (52 mg, 0.24 mmol) and DMAP (4 mg, 40μmol) at room temperature. The reaction mixture was stirred for 1 h atthe same temperature prior to quenching with saturated NaHCO₃ solution.The aqueous phase was extracted with EtOAc twice and the combinedorganic phases were dried over anhydrous MgSO₄ and concentrated invacuo. The residue was purified by preparative TLC (hexanes/EtOAc=2:1)to give urethane XS-27′ (74 mg, 85%) as a white solid. The opticalpurity of urethane XS-27′ was determined as >99% ee by HPLC analysis(FIG. 1).

HPLC Condition. Column: chiralpak OJ-H; solvent system:hexanes/i-propanol/diethylamine=85%/15%/0.1%; flow rate=1.0 mL/min;detector=UV at 277 nm; retention time: 41.6 and 38.2 min for (R)- and(S)-enantiomers, respectively.

Synthesis of C12-C19 Building Block X-34

Aldehyde X-33 was obtained from Dess-Martin oxidation of alcohol XS-27with the procedure same as shown in section 3.1.

To a solution of trimethylsilyl acetylene (3.63 g, 37 mmol) in THF (30mL) was added slowly n-butyllithium (2.5 M in hexanes, 14.8 mL, 37 mmol)at −78° C. about 30 min. After 1 h, a solution of boron trifluorideetherate (5.6 g, 39.6 mmol) in THF (20 mL) was added over 30 min and themixture was stirred for another 1 h (Yamauchi, M.; Hirao, I. TetrahedronLett. 1983, 24, 391). A solution of aldehyde X-33 (3.6 g, 13.2 mmol) inTHF (20 mL) was added over another 30 min. The resulting mixture wasstirred at −78° C. for 3 h, then directly poured into a saturated NaHCO₃solution (300 mL), and extracted with EtOAc (200 mL×3) and hexanes (200mL×2). The extracts were washed with brine (300 mL), dried overanhydrous MgSO₄, and then passed through a pad of silica gel (40 g).Elution with hexanes/EtOAc (1:4, 500 mL) and concentration gave thecrude product, which was purified by silica gel column chromatography(hexanes/CH₂Cl₂=50:1→25:1→10:1→5:1→2:1), to give XS-28 (4.4 g) as ayellow oil.

(6R)-6-chloro-8-iodo-1-(trimethylsilyl)non-8-en-1-yn-3-ol (XS-28)

¹H NMR (500 MHz, CDCl₃) δ: 6.18 (s, 1H), 5.85 (s, 1H), 4.42 (d, J=6.0Hz, 1H), 4.24-4.12 (m, 1H), 2.77 (d, J=7.0 Hz, 2H), 2.12-1.94 (m, 2H),1.90-1.74 (m, 2H), 0.17 (s, 9H); ¹³C NMR (125 MHz, CDCl₃) δ: 128.9,106.0, 105.9, 90.1, 62.1, 60.5, 53.4, 34.3, 32.6, −0.16; HRMS (ESI) m/z:[M+H]⁺ calcd for C₁₂H₂₁ClIOSi, 371.0095. found, 371.0103.

To a solution of propargyl alcohol XS-28 (4.4 g, 11.8 mmol) in acetone(60 mL) was added NBS (3.15 g, 17.7 mmol) and silver nitrate AgNO₃ (0.4g, 2.36 mmol) at rt. After 1.0 h, the reaction mixture was diluted with200 mL EtOAc and quenched by 100 mL saturated aq. Na₂S₂O₃ solution. Theaqueous layer was extracted with EtOAc (2×100 mL) and the combinedorganic layer was washed with saturated Na₂S₂O₃ solution (2×100 mL) and200 mL brine. The organic solution was dried over anhydrous MgSO₄ andconcentrated under reduced pressure. The residue was passed through asilica gel pad with eluent (2:1 hexanes/EtOAc, 300 mL), to give crudeXS-29 (4.1 g, silica gel TLC R_(f)˜0.5 in 6:1 hexanes/EtOAc) as a yellowoil. The crude XS-29 was used for the next step without furtherpurification.

(6R)-1-bromo-6-chloro-8-iodonon-8-en-1-yn-3-ol (XS-29)

¹H NMR (500 MHz, CDCl₃) δ: 6.18 (s, 1H), 5.86 (s, 1H), 4.47 (q, J=7.5Hz, 1H), 4.22-4.12 (m, 1H), 2.77 (d, J=7.5 Hz, 2H), 2.08-1.96 (m, 2H),1.94-1.79 (m, 2H); ¹³C NMR (125 MHz, CDCl₃) δ: 129.0, 105.8, 80.4, 62.7,60.5, 53.4, 45.9, 34.3, 32.6; HRMS (ESI) m/z: [M+H]⁺ calcd forC₉H₁₂BrClIO, 376.8805. found, 376.8811.

To a solution of AlCl₃ (2.9 g, 21.8 mmol) in Et₂O (40 mL) was addedslowly DIBAL solution (1.0M in THF, 43.6 mL, 43.6 mmol) at 0° C. (Thewhite solid was precipitated out from the reaction mixture on addingDIBAL. The white solid dissolved with a continuous addition of DIBALsolution, and eventually the solution became clear yellow or whiteprecipitated yellow color). The reaction mixture was stirred for 10□ (40mL) was added slowly DIBAL solution (1.0M in THF, 43.6 mL, 43.6 mmol) atXS-29 from the previous step in ethyl ether Et₂O (40+20+10 mL) was addedslowly in the reaction mixture about 10 mins. After 1 h (TLC monitor forno SM left), the reaction mixture was cooled down to 0° C. and quenchedslowly by MeOH (20 mL). To the reaction mixture was added the 200 mLsaturated sodium potassium tartrate solution and then stirred vigorouslyfor overnight. The white aqueous layer was extracted with EtOAc (3×100mL) and combined organic layer was washed with 200 mL brine. The organiclayer was dried over anhydrous MgSO₄ and concentrated to dryness underreduced pressure. The residue was purified by silica gel columnchromatography (hexanes/Et₂O=50:1→25:1→10:1→5:1→2:1→1:1), to give XS-30(3.5 g) as a yellow oil.

(6R,E)-1-bromo-6-chloro-8-iodonona-1,8-dien-3-ol (XS-30)

¹H NMR (500 MHz, CDCl₃) δ: 6.38 (d, J=13.0 Hz, 1H), 6.25 (ddd, J=13.0,6.5, 3.5 Hz, 1H), 6.17 (s, 1H), 5.85 (s, 1H), 4.26-4.08 (m, 2H), 2.76(d, J=6.0 Hz, 2H), 2.04-1.67 (m, 4H); ¹³C NMR (125 MHz, CDCl₃) δ: 140.0,129.0, 107.8, 107.7, 105.9, 72.2, 71.2, 60.8, 60.6, 53.5, 53.4, 33.5,33.2, 33.0, 32.5; HRMS (ESI) m/z: [M+Na]⁺ calcd for C₉H₁₃BrClINaO,400.8781; found, 400.8780.

Alcohol XS-30 was subjected to Dess-Martin oxidation reaction. The crudeproduct was purified by silica gel column chromatography(hexanes/CH₂Cl₂=100:1→50:1→25:1→10:1→5:1→2:1), to yield trans-bromoenoneX-34 (3.0 g) as a light yellow oil.

(R,E)-1-bromo-6-chloro-8-iodonona-1,8-dien-3-one (X-34)

[c]D₂₀=+10.5 (c 1.0, CHCl₃); ¹H NMR (500 MHz, C₆D₆) δ: 6.93 (d, J=13.5Hz, 1H), 6.26 (d, J=14.0 Hz, 1H), 5.68 (s, 1H), 5.55 (s, 1H), 3.98-3.88(m, 1H), 2.32 (dd, J=15.0, 9.0 Hz, 1H), 2.26 (dd, J=15.0, 6.0 Hz, 1H),2.08 (ddd, J=18.0, 9.0, 5.0 Hz, 1H), 1.88 (ddd, J=18.0, 9.0, 6.0 Hz,1H), 1.78-1.67 (m, 1H), 1.58-1.46 (m, 1H); ¹³C NMR (125 MHz, C₆D₆) δ:194.5, 136.5, 129.0, 125.5, 106.1, 60.6, 53.6, 37.4, 31.0; HRMS (ESI)m/z: [M+H]⁺ calcd for C₉H₁₂BrClIO, 376.8805. found, 376.8800.

Synthesis Outlined in FIG. 13 Synthesis of Polyether PhenanthrolineLigands

To a mixture of NaH (60% dispersion in mineral oil, 0.40 g, 1.0 mmol,5.5 equiv.) in 18 mL of DMF at 0° C., was added 15-C-5 (1.25 mL, 3.5equiv.) and alcohol (1.0 mL, 3.5 equiv.). After 30 min, a solution of4,7-dichloro-2,9-dimethyl-1,10-phenanthroline ((a) Larsen, A. F.; Ulven,T. Org. Lett. 2011, 13, 3546, (b) Schmittel, M.; Ammon, H. Eur. J. Org.Chem. 1998, 5, 785) (0.50 g, 1.8 mmol) in a 1:1 mixture of DMF and THF(total: 16 mL) was slowly added. After addition, the purple solution waswarmed to room temperature and stirred for 3 h. The reaction wasquenched with addition of 10 mL of water at 0° C., and concentratedunder vacuum. The residue was purified on Wakogel (50NH₂; eluted withfirst 1:1 hexanes/EtOAc, then pure EtOAc, finally 10:1 EtOAc/MeOH), togive the desired product as a yellow solid.

4,7-bis(2-methoxyethoxy)-2,9-dimethyl-1,10-phenanthroline (XS-31)

The desired product (0.22 g, 34% yield) was obtained from2-methoxyethanol. m.p. 115-117° C.; ¹H NMR (500 MHz, CDCl₃) δ: 8.11 (s,2H), 6.86 (s, 2H), 4.37 (t, J=5.0 Hz, 4H), 3.93 (t, J=5.0 Hz, 4H), 3.52(s, 6H), 2.88 (s, 6H); ¹³C NMR (125 MHz, CDCl₃) δ: 161.5, 160.1, 145.7,119.4, 118.1, 103.4, 70.6, 67.9, 59.4, 26.4; HRMS (ESI) m/z: [M+H]⁺calcd for C₂₀H₂₅N₂O₄, 357.1814. found, 357.1831.

4,7-bis(2-(2-methoxyethoxy)ethoxy)-2,9-dimethyl-1,10-phenanthroline(XS-32)

The desired product (0.47 g, 58% yield) was obtained from2-(2-methoxyethoxy)ethanol. m.p. 91-93° C.; ¹H NMR (500 MHz, CDCl₃) δ:8.10 (s, 2H), 6.85 (s, 2H), 4.39 (t, J=5.0 Hz, 4H), 4.04 (t, J=5.0 Hz,4H), 3.80 (m, 4H), 3.60 (m, 4H), 3.40 (s, 6H), 2.87 (s, 6H); ¹³C NMR(125 MHz, CDCl₃) δ: 161.2, 159.8, 145.7, 119.1, 117.8, 103.2, 71.7,70.6, 69.2, 67.6, 58.8, 26.3; HRMS (ESI) m/z: [M+H]⁺ calcd forC₂₄H₃₃N₂O₆ 445.2339. found, 445.2361.

4,7-bis(2-(2-(2-methoxyethoxy)ethoxy)ethoxy)-2,9-dimethyl-1,10-phenanthroline(X-37c)

The desired product (0.94 g, 98% yield) was obtained from triethyleneglycol monomethyl ether. m.p. 63-64° C.; ¹H NMR (500 MHz, CDCl₃) δ: 8.06(s, 2H), 6.81 (s, 2H), 4.33 (t, J=5.5 Hz, 4H), 3.99 (t, J=5.0 Hz, 4H),3.77 (m, 4H), 3.67 (m, 4H), 3.62 (m, 4H), 3.50 (m, 4H), 3.32 (s, 6H),2.83 (s, 6H); ¹³C NMR (125 MHz, CDCl₃) δ: 160.8, 159.4, 145.3, 118.8,117.4, 102.8, 71.2, 70.3, 70.0, 69.9, 68.7, 67.3, 58.3, 25.9; HRMS (ESI)m/z: [M+H]⁺ calcd for C₂₈H₄₁N₂O, 533.2863. found, 533.2879.

Preparation of NiCl₂ Complexes X-37a-c

To a stirred suspension of NiCl₂.DME (7.9 mg, 0.036 mmol) in 0.5 mL ofMeCN was slowly added the phenanthroline ligand XS-31 (13.4 mg, 0.038mmol) in 0.5 mL of MeCN. During the reaction, the Ni-complex precipitateout, which was filtered and dried under vacuum. The complex X-37a wasobtained as a purple powder in 12.2 mg, which can be used directly forthe Ni/Cr-mediated coupling reaction.

To a stirred suspension of NiCl₂.DME (7.9 mg, 0.036 mmol) in 0.5 mL ofMeCN was slowly added the phenanthroline ligand XS-32 (16.7 mg, 0.038mmol) in 0.5 mL of MeCN. The resulting clear purple solution was stirredfor 24 h at rt, then filtered, concentrated, and dried under highvacuum. The complex X-37b was obtained as a purple paste in 21.6 mg,which can be used directly for the Ni/Cr-mediated coupling reaction.

To a stirred suspension of NiCl₂-DME (7.9 mg, 0.036 mmol) in 0.5 mL ofMeCN was slowly added the phenanthroline ligand XS-33 (20.0 mg, 0.038mmol) in 0.5 mL of MeCN. The resulting clear purple solution was stirredfor 24 h at rt, then filtered, concentrated, and dried under highvacuum. The complex X-37c was obtained as a purple paste in 25.3 mg,which can be used directly for the Ni/Cr-mediated coupling reaction.

Synthesis of X-36 from Ni/Cr-Mediated Coupling Reaction Between X-34 andX-35

Preparation of Chromium Sulfonamide Solution:

In a glove box, to a 50 mL round-bottom flask, was added chiralsulfonamide X-12 (1.20 g, 2.2 mmol), proton sponge (Aldrich, purified bysublimation; 542.2 mg, 2.2 mmol) and CrCl₂ (Aldrich, 99.99% mg, 246 mg,2.0 mmol), and MeCN (Baker, ultra low water; 30.0 mL). The mixture wasstirred for 60 min at rt under nitrogen and changed to a deep greenhomogeneous solution which is ready to use for coupling reaction.

To a 250 mL round-bottom flask with C1-C11 aldehyde X-35 (7.09 g, 20mmol), was added LiCl (Aldrich, anhydrous, grinded; 1.70 mg, 40 mmol),Mn powder (Aldrich, 99.99%, powder; 2.20 g, 40 mmol), Zr(cp)₂Cl₂(Aldrich, 98%; 8.77 g, 30 mmol) and a solution of bromoenone X-34 (11.3g, 30 mmol) in MeCN (Baker, ultra low water; 25.0 mL). Then, a redMeCN-solution of NiCl₂-catalyst X-37c (6.70 mg, 0.01 mmol, 0.05 mol %;2.0 mL MeCN (Baker, ultra low water) was added and, lastly, the deepgreen solution of Cr-catalyst was transferred from the first flask tothe reaction flask with syringe. The reaction mixture was stirred undernitrogen for 3 h, and diluted with EtOAc (60 mL). Florisil (ca. 1.0 g)was added, and the mixture was stirred for 30 min, filtered through asilica gel pad (ca. 60 g) using EtOAc/hexanes (1:1). The eluent wasconcentrated in vacuo to furnish the crude coupling product, which canbe used for the next step without further purification.

Coupling Product X-36:

yellow oil; [α]_(D) ²⁰=−11.8 (c 0.65, CHCl₃); ¹H NMR (500 MHz, C₆D₆) δ:7.16 (dd, J=16.0, 4.0 Hz, 1H), 6.54 (dd, J=16.0, 1.5 Hz, 1H), 5.73 (d,J=1.5 Hz, 1H), 5.57 (d, J=1.5 Hz, 1H), 4.50 (dd, J=5.0, 1.0 Hz, 1H),4.21 (dd, J=8.0, 3.5 Hz, 1H), 4.16 (d, J=8.5 Hz, 1H), 4.12-4.04 (m, 1H),4.02 (dt, J=11.0, 5.0 Hz, 1H), 3.81-3.72 (m, 1H), 3.30 (s, 3H), 3.26 (d,J=7.5 Hz, 1H), 3.03 (dd, J=10.0, 2.5 Hz, 1H), 2.54 (ddd, J=18.0, 8.5,5.0 Hz, 1H), 2.47 (dd, J=16.0, 8.0 Hz, 1H), 2.44 (ddd, J=18.0, 9.0, 7.0Hz, 1H), 2.36 (d, J=7.0 Hz, 2H), 2.47 (dd, J=16.0, 4.5 Hz, 1H),2.30-2.24 (m, 1H), 1.98-1.87 (m, 2H), 1.85-1.68 (m, 4H), 1.62-1.50 (m,2H), 1.49-1.38 (m, 4H), 1.34-1.18 (m, 2H), 1.17-1.00 (m, 2H); ¹³C NMR(125 MHz, C₆D₆) δ: 197.7, 171.1, 146.2, 129.1, 128.8, 110.7, 106.3,76.1, 75.0, 74.4, 72.6, 71.7, 71.2, 66.7, 61.0, 53.6, 51.1, 40.3, 36.2,33.9, 30.8, 30.1, 25.4, 24.3, 23.9; HRMS (ESI) m/z: [M+H]⁺ calcd forC₂₇H₃₉ClIO₈, 653.1378; found, 653.1369.

Synthesis Outlined in FIG. 14

To a mixture of sulfonamide X-12 (2.60 mg, 5.5 mol), proton sponge(Aldrich, purified by sublimation; 1.18 mg, 5.5 μmol) and CrCl₂(Aldrich, 99.99% mg, 0.62 mg, 5.0 μmol) was added MeCN (Baker, ultra lowwater; 50 μL) in a glovebox. The mixture was stirred for 60 min at rtunder nitrogen. To the second new vial were added Zr(cp)₂Cl₂ (Aldrich,98%; 21.9 mg, 75 μmol), Mn powder (Aldrich, 99.99%, powder; 5.5 mg, 100μmol), LiCl (Aldrich, anhydrous, grinded; 4.3 mg, 100 μmol), aldehyde(16.4 mg, 50 μmol), trans-bromoenone X-34 (75 μmol) and McCN (Baker,ultra low water; 75 μL). Ni-catalyst X-37c (0.033 mg, 0.05 μmol) wasadded as a solution of MeCN (2.0 mg/mL, 16 μL). The mixture in the firstvial was transferred to the second vial with syringe under nitrogen. Thereaction mixture was stirred under nitrogen until the reaction wascompleted (TLC monitor) about 3 h, and diluted with EtOAc (1.0 mL).Florisil (ca. 30 mg) was added, and the mixture was stirred for 30 min,filtered through a short silica gel pad with 1:1 EtOAc/hexanes. Theeluent was concentrated in vacuo to furnish the crude coupling product,which was purified by preparative TLC (EtOAc/hexanes=1:4) to give thedesired product as a yellow liquid.

(E)-13-((tert-butyldiphenylsilyl)oxy)-4-chloro-10-hydroxy-2-iodotrideca-1,8-dien-7-one(XS-34)

¹H NMR (500 MHz, C₆D₆) δ: 7.79-7.68 (m, 4H), 7.26-7.17 (m, 6H), 6.60(dd, J=16.0, 4.0 Hz, 1H), 6.22 (dd, J=16.0, 1.5 Hz, 1H), 5.69 (d, J=1.5Hz, 1H), 5.54 (d, J=1.5 Hz, 1H), 4.10-4.01 (m, 1H), 3.91-3.83 (m, 1H),3.54 (t, J=6.0 Hz, 2H), 2.43 (ddd, J=17.5, 9.0, 5.0 Hz, 1H), 2.34 (t,J=4.0 Hz, 2H), 2.30 (ddd, J=17.5, 8.5, 6.5 Hz, 1H), 1.97-1.85 (m, 1H),1.78 (br, 1H), 1.52-1.28 (m, 5H), 1.13 (s, 9H); ¹C NMR (125 MHz, C₆D₆)δ: 197.6, 148.0, 135.9, 133.9, 130.1, 128.9, 128.5, 128.3, 106.3, 70.7,64.3, 61.0, 53.6, 37.6, 33.8, 31.6, 28.7, 27.0, 19.4; HRMS (ESI) m/z:[M+Na]⁺ calcd for C₂₉H₃₈ClINaO₃Si, 647.1221. found, 647.1233.

(E)-1-((tert-butyldimethylsilyl)oxy)-8-chloro-2-hydroxy-10-iodoundeca-3,10-dien-5-one(X-37)

¹H NMR (500 MHz, CDCl₃) δ: 6.78 (dd, J=16.0, 4.5 Hz, 1H), 6.43 (dd,J=16.0, 2.0 Hz, 1H), 6.18 (d, J=1.5 Hz, 1H), 5.85 (d, J=1.5 Hz, 1H),4.45-4.34 (m, 1H), 4.22-4.12 (m, 1H), 3.75 (dd, J=10.0, 3.5 Hz, 1H),3.50 (dd, J=10.0, 7.0 Hz, 1H), 2.94-2.66 (m, 4H), 2.26-2.15 (m, 1H),1.97-1.85 (m, 1H), 0.90 (s, 9H), 0.08 (s, 6H); ¹³C NMR (125 MHz, CDCl₃)δ: 194.5, 136.5, 129.0, 125.5, 106.1, 60.6, 53.6, 37.4, 31.0; HRMS (ESI)m/z: [M+Na]⁺ calcd for C₁₇H₃₀ClINaO₃Si, 495.0595. found, 495.0613.

(E)-7-chloro-1-cyclohexyl-1-hydroxy-9-iododeca-2,9-dien-4-one (X-38)

¹H NMR (500 MHz, C₆D₆) δ: 6.65 (dd, J=16.0, 5.0 Hz, 1H), 6.15 (dd,J=16.0, 1.5 Hz, 1H), 5.69 (d, J=1.0 Hz, 1H), 5.54 (d, J=1.5 Hz, 1H),4.13-4.05 (m, 1H), 3.95-3.87 (m, 1H), 3.58 (t, J=6.0 Hz, 2H), 2.46 (ddd,J=18.0, 9.0, 5.0 Hz, 1H), 2.34 (t, J=4.0 Hz, 2H), 2.30 (ddd, J=18.0,9.0, 7.0 Hz, 1H), 1.98-1.89 (m, 1H), 1.76-1.65 (m, 1H), 1.64-1.54 (m,3H), 1.53-1.47 (m, 1H), 1.46-1.39 (m, 1H), 1.19-1.10 (m, 1H), 1.09-0.94(m, 2H), 0.93-0.80 (m, 2H); ¹³C NMR (125 MHz, C₆D₆) δ: 197.5, 147.1,128.9, 128.8, 128.5, 106.3, 75.4, 61.0, 53.6, 43.8, 37.6, 31.6, 29.2,28.0, 26.6, 26.4, 26.3; HRMS (ESI) m/z: [M+H]⁺ calcd for C₁₆H₂₅ClIO₂,411.0588. found, 411.0580.

(E)-7-chloro-1-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-1-hydroxy-9-iododeca-2,9-dien-4-one(X-39)

¹H NMR (500 MHz, CDCl₃) δ: 6.81 (dd, J=16.0, 4.0 Hz, 1H), 6.46 (dd,J=16.0, 2.0 Hz, 1H), 6.18 (d, J=2.0 Hz, 1H), 5.85 (d, J=2.0 Hz, 1H),4.53-4.46 (m, 1H), 4.20-4.12 (m, 2H), 3.95 (t, J=7.5 Hz, 1H), 3.88 (dd,J=9.0, 6.5 Hz, 1H), 2.94-2.79 (m, 2H), 2.77 (d, J=7.5 Hz, 2H), 2.43 (d,J=3.5 Hz, 1H), 2.25-2.15 (m, 1H), 1.96-1.85 (m, 1H), 1.45 (s, 3H), 1.36(s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ: 198.4, 142.8, 129.4, 129.0, 109.8,105.6, 77.3, 70.6, 64.7, 60.5, 53.6, 37.6, 31.0, 26.4, 24.9; HRMS (ESI)m/z: [M+Na]⁺ calcd for C₁₅H₂₂ClINaO₄, 451.0149. found, 451.0141.

(E)-4-chloro-10-hydroxy-2-iodo-12-methyltrideca-1,8,11-trien-7-one(X-40)

¹H NMR (500 MHz, CDCl₃) δ: 6.78 (dd, J=16.0, 4.5 Hz, 1H), 6.31 (dd,J=16.0, 1.5 Hz, 1H), 6.19 (d, J=1.5 Hz, 1H), 5.85 (d, J=1.5 Hz, 1H),5.17-5.12 (m, 1H), 5.09-5.04 (m, 1H), 4.20-4.12 (m, 1H), 2.93-2.75 (m,4H), 2.25-2.16 (m, 1H), 1.95-1.86 (m, 1H), 1.76 (d, J=1.0 Hz, 3H), 1.74(d, J=1.0 Hz, 3H), 1.64 (d, J=3.5 Hz, 1H); ¹³C NMR (125 MHz, CDCl₃) δ:199.1, 146.9, 137.7, 129.0, 127.5, 124.1, 105.7, 68.4, 60.6, 53.6, 37.2,31.1, 25.8, 18.4; HRMS (ESI) m/z: [M+Na]⁺ calcd for C₁₄H₂ClINaO₂,405.0094. found, 405.0085.

(E)-9-chloro-3-hydroxy-11-iodo-1-phenyldodeca-4,11-dien-6-one (X-41)

1H NMR (500 MHz, CDCl₃) δ: 7.32-7.27 (m, 2H), 7.23-7.17 (m, 3H), 6.84(dd, J=16.0, 5.0 Hz, 1H), 6.32 (dd, J=16.0, 1.0 Hz, 1H), 6.19 (d, J=1.0Hz, 1H), 5.86 (d, J=1.5 Hz, 1H), 4.39-4.32 (m, 1H), 4.19-4.12 (m, 1H),2.91-2.68 (m, 6H), 2.26-2.14 (m, 1H), 1.99-1.84 (m, 3H), 1.75 (d, J=4.0Hz, 1H); ¹³C NMR (125 MHz, CDCl₃) δ: 198.8, 148.0, 141.1, 129.0, 128.5,128.4, 128.0, 126.1, 105.6, 70.4, 60.5, 53.6, 38.0, 37.4, 31.4, 31.1;HRMS (ESI) m/z: [M+Na]⁺ calcd for C₁₈H₂₂ClINaO₂, 455.0251. found,455.0245.

(E)-7-chloro-1-hydroxy-9-iodo-1-phenyldeca-2,9-dien-4-one (X-42)

¹H NMR (500 MHz, CDCl₃) δ: 7.45-7.31 (m, 5H), 6.94 (dd, J=16.0, 5.0 Hz,1H), 6.45 (dd, J=16.0, 1.5 Hz, 1H), 6.17 (s, 1H), 5.85 (s, 1H), 5.40 (s,1H), 4.22-4.12 (m, 1H), 2.95-2.72 (m, 4H), 2.26-2.12 (m, 2H), 1.96-1.84(m, 1H); ¹³C NMR (125 MHz, CDCl₃) δ: 198.9, 146.6, 140.8, 129.0, 128.9,128.5, 127.8, 126.5, 105.6, 73.7, 60.5, 53.6, 37.4, 31.1; HRMS (ESI)m/z: [M+Na]⁺ calcd for C₁₆H₁₈ClINaO₂, 426.9938. found, 426.9951.

(E)-7-chloro-1-(furan-2-yl)-1-hydroxy-9-iododeca-2,9-dien-4-one (X-43)

¹H NMR (500 MHz, C₆D₆) δ: 7.01 (d, J=1.0 Hz, 1H), 6.76 (dt, J=16.0, 4.0Hz, 1H), 6.29 (dt, J=16.0, 2.0 Hz, 1H), 6.00 (t, J=2.5 Hz, 1H), 5.97 (t,J=3.6 Hz, 1H), 5.72 (s, 1H), 5.57 (s, 1H), 4.92 (s, 1H), 4.07-3.98 (m,1H), 2.44-2.29 (m, 4H), 2.28-2.18 (m, 1H), 1.93-1.82 (m, 1H), 1.73-1.62(m, 1H); ¹³C NMR (125 MHz, C₆D₆) δ: 197.4, 154.2, 143.0, 142.6, 129.3,128.9, 110.6, 107.4, 106.3, 67.1, 60.8, 53.6, 37.5, 31.4; HRMS (ESI)m/z: [M+Na]⁺ calcd for C₁₄H₁₆ClINaO₃, 416.9730. found, 416.9733.

(13S,E)-4,13-dichloro-10-hydroxy-2,15-diiodohexadeca-1,8,15-trien-7-one(XS-35)

¹H NMR (500 MHz, CDCl₃) δ: 6.85 (dd, J=15.5, 5.0 Hz, 1H), 6.46 (dd,J=15.5 Hz, 1.0 Hz, 1H), 6.19 (d, J=1.5 Hz, 1H), 6.17 (d, J=1.5 Hz, 1H),5.85 (t, J=2.0 Hz, 2H), 4.46-4.38 (m, 1H), 4.20-4.12 (m, 2H), 2.94-2.79(m, 2H), 2.78 (d, J=7.0 Hz, 2H), 2.76 (d, J=7.0 Hz, 2H), 2.26-2.16 (m,1H), 1.99-1.76 (m, 6H); ¹³C NMR (125 MHz, CDCl₃) δ: 198.8, 147.6, 129.1,128.3, 105.9, 105.6, 70.3, 60.6, 60.5, 53.6, 53.4, 37.5, 33.0, 32.5,31.1; HRMS (ESI) m/z: [M+Na]⁺ calcd for C₁₆H₂₂Cl₂I₂NaO₂, 592.8984.found, 592.8980.

Synthesis Outlined in FIG. 15

To a solution of X-36 (11.4 g, 17.5 mmol) in CH₂Cl₂ (175 mL) were addedpyridine (4.5 mL, 52.5 mmol), PNBCl (6.5 g, 35.0 mmol), and DMAP (214mg, 1.75 mmol) at 0° C., and the reaction mixture was warmed to roomtemperature. After stirring for 12 h, the solvent of reaction mixturewas removed under reduced pressure and then passed through the silicagel pad with eluent of hexanes/EtOAc (1:1, 1500 mL). The eluent wasremoved to give the crude product XS-36, which can be used for the nextstep without further purification.

PNB XS-36:

yellow oil; [α]_(D) ²⁰=−26.5 (c 0.40, CHCl₃); ¹H NMR (500 MHz, C₆D₆) δ:7.84 (d, J=8.0 Hz, 2H), 7.72 (d, J=8.0 Hz, 2H), 7.23 (dd, J=16.0, 5.0Hz, 1H), 6.41 (dd, J=16.0, 1.0 Hz, 1H), 6.08 (dt, J=5.0, 1.0 Hz, 1H),5.71 (s, 1H), 5.56 (s, 1H), 4.30 (dd, J=8.0, 3.0 Hz, 1H), 4.08 (d,J=10.5 Hz, 1H), 4.08-3.98 (m, 1H), 3.84-3.76 (m, 1H), 3.64 (dd, J=6.5,1.5 Hz, 1H), 3.31 (s, 3H), 3.09 (dd, J=10.5, 3.0 Hz, 1H), 2.49 (ddd,J=18.0, 9.0, 6.5 Hz, 1H), 2.47 (dd, J=16.0, 8.0 Hz, 1H), 2.38 (ddd,J=18.0, 9.0, 7.0 Hz, 1H), 2.33 (d, J=6.5 Hz, 2H), 2.00 (dd, J=16.0, 4.0Hz, 1H), 1.92-1.72 (m, 4H), 1.68-1.58 (m, 2H), 1.42-1.13 (m, 9H),1.10-0.96 (m, 2H); ¹³C NMR (125 MHz, C₆D₆) δ: 197.2, 171.1, 163.3,150.9, 140.9, 134.8, 130.9, 130.6, 128.9, 123.7, 111.1, 106.2, 75.9,75.1, 74.3, 73.6, 71.8, 71.7, 66.9, 60.8, 53.6, 51.1, 40.2, 36.2, 33.8,30.7, 30.0, 25.3, 24.3, 23.8; HRMS (ESI) m/z: [M+H]⁺ calcd forC₃₄H₄₂ClINO₁₁, 802.1491. found, 802.1499.

To the crude product XS-36 from the previous step was added a solventmixture of 4:1:5 TFA/H₂O/CH₂C₂ (950 mL). The reaction mixture wasstirred for 2 h (TLC monitor), and then poured in small portions intosaturated aq. NaHCO₃ solution (1000 mL). The aqueous mixture solutionwas neutralized with excess amount of solid NaHCO₃, and extracted withEtOAc (500 mL×5). The combined organic layer was washed with saturatedNaHCO₃ solution, saturated NH₄Cl solution, brine, and dried over MgSO₄.The solvent was removed to give crude product XS-37, which can be usedfor the next step without further purification.

XS-37-major:

yellow oil; [α]_(D) ²⁰=+1.0 (c 0.37, CHCl₃); ¹H NMR (500 MHz, C₆D₆) δ:8.19 (d, J=9.0 Hz, 2H), 7.68 (d, J=9.0 Hz, 2H), 5.69 (d, J=1.5 Hz, 1H),5.55 (d, J=1.5 Hz, 1H), 5.52-5.56 (m, 1H), 4.20-4.12 (m, 2H), 4.08 (dd,J=10.0, 5.0 Hz, 1H), 4.02 (dt, J=10.0, 5.0 Hz, 1H), 3.99-3.93 (m, 1H),3.81-3.73 (m, 1H), 3.66 (dd, J=10.0, 5.0 Hz, 1H), 3.29 (s, 3H), 2.83 (s,1H), 2.73 (dd, J=10.0, 2.5 Hz, 1H), 2.53 (dd, J=15.5, 3.0 Hz, 1H), 2.39(dd, J=17.0, 7.5 Hz, 1H), 2.30 (dt, J=15.0, 8.0 Hz, 1H), 2.28 (dt,J=14.0, 6.0 Hz, 1H), 2.19 (dd, J=17.0, 6.0 Hz, 1H), 2.17-1.97 (m, 2H),1.88-1.76 (m, 2H), 1.56-1.44 (m, 1H), 1.32-1.18 (m, 2H), 1.15-1.02 (m,1H), 0.96-0.82 (m, 1H); ¹³C NMR (125 MHz, C₆D₆) δ: 204.4, 170.9, 164.0,151.0, 134.6, 131.1, 128.9, 123.9, 105.9, 77.3, 75.1, 74.8, 74.7, 73.7,73.2, 65.9, 65.4, 60.6, 53.4, 51.0, 42.0, 40.3, 39.6, 30.8, 30.2, 30.0;HRMS (ESI) m/z: [M+H]⁺ calcd for C₂₈H₃₄ClONO₁₁, 722.0865. found,722.0860.

To a solution of crude product XS-37 from the previous step in 50 mLCH₂Cl₂ was added a mixture of 18:1 MeOH/H₂O (950 mL) and Na₂CO₃ solid(10.6 g, 100 mmol). The reaction mixture was stirred until the reactionwas completed (TLC monitor) about 6 h. The reaction mixture was dilutedwith 500 mL Et₂O and passed through a pad of Celite to remove whitesolid. The eluent was concentrated under reduced pressure, to give thecrude product, which was purified by flash silica gel columnchromatography (hexanes/EtOAc=20: 1-1:2), to give a mixture ofdiastereomers (X-45: X-44=2:1; 8.2 g) as a yellow liquid.

Preparation of Ion-Exchange Resin Device

((a) Namba, K.; Jun, H. S.; Kishi, Y. J. Am. Chem. Soc. 2004, 126, 7770,(b) Kaburagi, Y.; Kishi, Y. Org. Lett. 2007, 9, 723.): A cartridgecolumn (Biotage, 25 g) was cleaned, filled with polymer-bound pyridiniump-toluenesulfonate resin (20.0 g, Aldrich #82817, −3.5 mmol/g toluene4-sulfonate loading), dehydrating reagent, 3 Å molecular sieves (FisherSci, 3.0 g) and another cartridge column (Biotage, 25 g) was cleaned,filled with polymer-bound1,3,4,6,7,8-hexahydro-2H-pyrimido[1,2-a]pyrimi-dine resin (20.0 g,Aldrich #358754, 2.6 mmol/g loading, 2% cross-linked withdivinylbenzene) and washed with 100 mL 200 proof pure EtOH (Koptec,V1016).

The mixture of X-44 and X-45 (8.2 g) was dissolved in 500 mL EtOH in a2000 mL round flask. A pump, reaction flask and ion-exchange column wereconnected as shown in FIG. 2. The mixture (10 mg/mL solution in EtOH)was circulated for 10 h (flow rate: 2 mL/min). The column was washedwith ethanol (300 mL). The combined EtOH solutions were concentratedunder reduced pressure. The residue was passed through a short silicagel plug (elution with hexanes/EtOAc=10:1 to 1:1) to give product X-46as a yellow oil.

C1-C19 BB of Halichondrin Bs X-46:

yellow oil, [α]_(D) ²⁰=−25.8 (c 1.0, CHCl₃); ¹H NMR (500 MHz, C₆D₆) δ:5.83 (s, 1H), 5.67 (s, 1H), 4.41 (dt, J=10.0, 4.0 Hz, 1H), 4.02 (dt,J=10.0, 5.0 Hz, 1H), 4.36 (s, 1H), 4.14 (sep, J=5.0 Hz, 2H), 4.08 (t,J=5.0 Hz, 1H), 3.89 (dd, J=6.5, 5.0 Hz, 1H), 3.76-3.69 (m, 1H), 3.66(dd, J=6.5, 4.0 Hz, 1H), 3.30 (s, 3H), 2.58 (dt, J=15.0, 5.0 Hz, 2H),2.51 (dd, J=15.5, 3.0 Hz, 1H), 2.17 (dd, J=16.0, 5.0 Hz, 1H), 2.22-2.12(m, 1H), 2.10-1.75 (m, 5H), 1.44-1.37 (m, 1H), 1.35 (dd, J=13.0, 5.0 Hz,1H), 1.33-1.16 (m, 2H); ¹³C NMR (125 MHz, C₆D₆) δ: 170.9, 128.8, 109.7,106.8, 82.4, 80.8, 78.5, 76.9, 74.9, 74.7, 74.2, 68.5, 61.8, 53.4, 51.1,47.4, 40.7, 36.3, 32.4, 30.8, 30.7; HRMS (ESI) m/z: [M+H]⁺ calcd forC₂₁H₂₉ClIO₇, 555.0646. found, 555.0655.

Synthesis of C1-C19 Thioester for X-Ray Structure Determination

The C1-C19 carboxylic ester X-46 (200 mg, 0.37 mmol) was dissolved in3.7 mL of freshly distilled 1,2-dichloroethane and after addition ofMe₃SnOH (532 mg, 2.94 mmol), the mixture was heated to 80° C. until TLCanalysis indicated a complete reaction (about 48 h). After completion ofthe reaction, the mixture was concentrated in vacuo, and the residue wastaken up in 100 mL EtOAc. The organic layer was washed with aqueous 1NHCl solution (20 mL×3) and then washed with brine (15 mL) and dried overanhydrous MgSO₄. Removal of the solvent in vacuo afforded the crudeproduct C1-C19 carboxylic acid, which was used directly for the nextstep without further purification (Nicolaou, K. C.; Estrada, A. A.; Zak,M.; Lee, S. H.; Safina, B. S. Angew. Chem. Int. Ed. 2005, 44, 1378).

To the solution of crude C1-C19 carboxylic acid product from theprevious step in anhydrous CH₂Cl₂ (37 mL) was added DCC (169.3 mg, 0.74mmol), methyl 2-mercaptoacetate (58.9 mg, 0.56 mmol) and DMAP (5.0 mg,0.0387 mmol). The reaction mixture was stirred at rt for 4 h (TLCmonitor), filtered through a short Celite pad and the eluent wasconcentrated under reduced pressure. The residue was purified by flashchromatography (EtOAc/hexane=1:1) to give the product XS-38 as a whitesolid (90% yield) (Xiao, J. P.; Tolbert, T. J. Org. Lett. 2009, 11,4144). Compound XS-38 was obtained from the mixture solvent (hexanes andEtOAc) and subjected to X-ray analysis (FIG. 3).

Coupling Efficiency of β-Haloenones with Aldehydes

The synthesis of C1-C19 building block X-D relies on a C—C bondformation between aldehyde X-A with a vinylogous acyl anion generatedfrom β-haloenone X-B. There are several methods reported for C—C bondformation between “masked” vinylogous acyl anions and aldehydes (Cohen,T.; Bennett, A. B.; Mura, Jr., A. J. J. Org. Chem. 1976, 41, 2506. (b)Debal, A.; Cuvigny, T.; Larcheveque, Tetrahedron Lett. 1977, 36, 3187;Piers, E.; Morton, H. E. J. Org. Chem. 1979, 44, 3437. (d) Ren, H.;Krasovskiy, A.; Knochel, P. Org. Lett. 2004, 6, 4215). In 1992, acoupling reaction between methyl β-iodoacrylate X-2 and aldehyde X-1 wasreported, which allowed the effective formation of the C29-C30 bond ofhalichondrins. Since then, the original stoichiometric, non-asymmetricreaction to the catalytic, asymmetric version has been improved (Aicher,T. D.; Buszek, K. R.; Fang, F. G.; Forsyth, C. J.; Jung, S. H.; Kishi,Y.; Scola, P. M. Tetrahedron Lett. 1992, 33, 1549. (b) Chen, C.; Tagami,K.; Kishi, Y. J. Org. Chem. 1995, 60, 5386. (c) Namba, K.; Kishi, Y Org.Lett. 2004, 6, 5031. (d) Guo, H.; Dong, C.-G.; Kim, D.-S.; Urabe, D.;Wang, J.; Kim, J. T.; Liu, X.; Sasaki, T.; Kishi, Y. J. Am. Chem. Soc.2009, 131, 15387). Knochel and Rao disclosed a coupling ofβ-iodocyclohexenone X-4 with aldehydes in the presence of CrCl₂ in DMF(Knochel, P.; Rao, C. J. Tetrahedron, 1993, 49, 29). In connection withthe synthetic efforts on the taxane class of natural products, theNi/Cr-mediated coupling reaction was used to construct the taxane ringsystem, cf., X-7→X-8 (Kress, M. H.; Ruel, R.; Miller, W. H.; Kishi, YTetrahedron Lett. 1993, 34, 6003; Michael H. Kress, “Applications of theNi(II)/Cr(II)-Mediated Coupling Reaction to the Synthesis of the TaxaneDiterpenes” (January, 1995, Harvard University). (2) XiaoningChristopher Sheng, “Total Synthesis of (+)-Cinnamoyltaxicin-ITriacetate” (September, 1998, Harvard University). (3) Jongwon Lim,“Total Synthesis of Taxol” (July, 2000, Harvard University)). Theseexamples relied on Cr-organometallics. Based on this observation,Ni/Cr-mediated coupling was focused on, to realize the couplingX-A+X-B→X-C.

The first phase of the study was to assess the coupling efficiency ofβ-iodoenones with aldehydes, with use of model substrates (FIG. 7). Thecoupling efficiency between β-iodoenone X-9a and aldehyde X-10 with 10mol % Cr-catalyst, prepared from (S)-sulfonamide X-12, and 1 mol %(Me)₂Phen(H)₂.NiCl₂ X-13a in MeCN (FIG. 7) was tested.

β-Iodoenone X-9a was compared with β-bromo- and 1-chloroenones X-9b,c.X-9b,c might be less reactive than X-9a because of electronic effectsand, therefore, might have a better reactivity-balance between the Ni-and Cr-catalytic cycles. This experiment showed that: (1) X-9b,c gave abetter coupling efficiency than X-9a and (2) X-9b gave a slightly bettercoupling efficiency than X-9c.

β-bromoenone X-9b was used to conduct a second experiment. The overallcoupling efficiency with less reactive Ni-catalyst and, then, with alesser amount of the Ni-catalyst was tested. (Me)₂Phen(OMe)₂.NiCl₂ X-13bis a slower activator, based on previous studies, of vinyl iodides than(Me)₂Phen(H)₂.NiCl₂ X-13a (Liu, X.; Li, X.; Yu Chen, Hu, Y; Kishi, Y. J.Am. Chem. Soc. 2012, 134, 6136). On replacing X-13a with X-13b, thecoupling efficiency was noticeably improved. The ratio of Ni- overCr-catalysts was optimized; with 10 mol % Cr-catalyst fixed, 1, 0.5.0.1, 0.05, and 0.01 mol % Ni-catalyst loadings were tested, therebyrevealing that: (1) the coupling efficiency improved with lowering theNi-catalyst loading and (2) the coupling efficiency reached the plateauat the 0.05-0.01 mol % Ni-catalyst loading. It is worthwhile noting thatthe coupling reaction did not proceed without Ni-catalysts.

The coupling condition of “10 mol % Cr-catalyst, prepared fromsulfonamide X-12, 0.05 mol % Ni-complex X-13b, Zr(cp)₂Cl₂ (1.5 eq), LiCl(2 eq), and Mn (2 eq) in MeCN ([C]0.4 M) at room temperature” is usedfor a study of coupling efficiency. FIG. 8 summarizes the couplingefficiency for di-substituted trans-β-bromoenones with aldehydes. Theproducts thus obtained were stable enough to isolate and characterize.However, on standing in benzene, methylene chloride, and other solvents,at room temperature, they gradually decomposed, to yield thecorresponding furans. With acid treatment (p-TSA or CSA/MeCN/RT), theygave the furans almost instantaneously. On acylation, however, thecoupling products became stable even in the presence of acids (aq. TFA,CH₂Cl₂, RT).

FIG. 9 summarizes applying this coupling reaction to other types of3-bromoenones. The first case studied was cis-β-bromoenone X-19; a ˜9:1mixture of coupling product X-11 was obtained, similar to the couplingproduct obtained from trans-β-bromoenone X-9b, and furan X-20. Transtri-substituted β-bromoenone X-21 gave a 1:1 mixture of coupling productX-23 and furan X-24, whereas cis tri-substituted β-bromoenone 22 gaveonly furan X-24.

Overall, the disclosed coupling reaction between an aldehyde and a“naked” vinylogous acyl anion is synthetically useful at least fordi-substituted trans-β-bromoenones. Interestingly, the method meets theneed to achieve the proposed coupling reaction X-A+X-B→X-C (FIG. 4).

Selective Activation of β-Bromoenone Over Vinyl Iodide and SaturatedChloride

FIG. 10 shows exemplary reported selective activation/coupling of apoly-halogenated nucleophile in the Ni/Cr-mediated coupling reactions isshown in FIG. 10. The first example shows that a selectiveactivation/coupling is possible with the use of selective activator inthe Cr-mediated couplings; namely, cobalt- and iron-salts are known toactivate saturated halides, but not vinyl halides (Takai, K.; Nitta, K.;Fujimura, O.; Utimoto, K. J. Org. Chem. 1989, 4732). The second exampleshows that a selective activation of iodoacetylene in the Ni/Cr-mediatedreaction is possible without disturbing the vinyl iodide present in theelectrophile.

Competition experiments were conducted to study the selectiveactivation/coupling. Aldehyde X-10 was coupled with a 1:1 mixture ofβ-bromoenone X-9b and vinyl iodide X-31a, b, or c in the presence of adifferent amount of Ni-catalysts X-13a,b, followed by ratio-analysis ofthe two expected products X-11 and X-32 (¹H NMR) (FIG. 11). Thecompetition experiments demonstrated that: (1) 0.05 and 0.1 mol %Ni-catalyst loadings, against 10 mol % Cr-catalyst loading, allowselectively to activate/couple β-bromoenone X-9b over all the threetypes of vinyl iodides X-31a-c and (2) Ni-catalyst X-13b gives a betterdiscrimination of β-bromoenone X-9b over vinyl iodides X-31a-c thanNi-catalyst X-13a. Interestingly, 0.05 and 0.1 mol % Ni-catalystloadings coincided with the Ni-catalyst amount ideal for β-bromoenonecouplings (see the previous section).

The coupling study of X-34 and X-35 can be found in FIG. 13. Requisitenucleophile 34 was readily prepared from the previously reported,optically pure aldehyde 33 (FIG. 12) (Liu, S.; Kim, J. T.; Dong, C.-G.;Kishi, Y. Org. Lett. 2009, 11, 4520). With respect to the electrophile,several possible protecting groups at C8 and C9 were tested, therebyshowing that the cyclohexylidene is the best option.

Aldehyde X-35 was subjected to the Ni/Cr-coupling reaction (10 mol %Cr-catalyst, prepared from sulfonamide X-12, and 0.05 mol % Ni-catalystX-13b), to furnish a single coupling product in 46% yield. Thespectroscopic analysis (HR-MS, ¹H NMR, and ¹³C NMR) demonstrated thatthe isolated product was the desired coupling product X-36. Inparticular, the C10-C11 vicinal proton spin-coupling constant (1.0 Hz)allowed for the assignment of the desired β-configuration to the newlyintroduced alcohol. Based on the previous examples similar to thepresent case, the desired diastereomer was anticipated to be formed in ahigh stereoselectivity with the Cr-catalyst prepared from(S)-sulfonamide X-12 (Aicher, T. D.; Kishi, Y. Tetrahedron Lett. 1987,28, 3463).

Three polyether-type phenanthrene.NiCl₂ complexes X-37a-c were prepared.The solubility of these complexes, particularly X-37b and X-37c, wasimproved. With the use of X-37c, the coupling yield was improved (Thecoupling yields with X-37a and X-37b were 59% and 75%, respectively. ANi-catalyst with n-dodecyloxy substituents is also prepared, i.e.,X=n-C12H25O in X-13, but found that its solubility was roughly same asthat of X-13b and the coupling yield with this Ni-catalyst was 60%).

FIG. 14 summarizes the coupling of β-bromoenone X-34 with variousaldehydes. Among them, the result with aldehyde X-33 shows a selectiveactivation of a 3-bromoenone over a vinyl iodide. Activation of vinyliodide in X-33 can induce cyclization with the aldehyde.

Synthesis of C1-C19 Building Block of Halichondrin Bs and AnalogsThereof

The coupling product X-36 was prone to furan-formation, but thisinstability could be overcome by acylation of the resultant allylicalcohol. Among several acyl groups tested, p-nitrobenzoate was chosen,because it was found to be stable under the aq. TFA condition requiredfor hydrolysis of the C8,C9-cyclohexylidene group, cf., step 2 in FIG.15.

On treatment with aqueous Na₂CO₃, the p-nitrobenzoate group of aq.TFA-hydrolysis product was smoothly hydrolyzed, followed by anoxy-Michael reaction of the C9 hydroxyl group to the α,β-unsaturatedketone, to furnish a ˜1:2 mixture of X-44 and X-45 (FIG. 15). In theprevious studies, the chemical behaviors of these oxy-Michael products,including: (1) PPTS treatment allows to convert the C12-β oxy-Michaelproduct X-45 to the desired polycycle, cf., X-46; (2) undesired C12-αoxy-Michael product X-44 can be recycled via retrooxy-Michael/oxy-Michael equilibration under basic condition; (3) anion-exchange resin based device allows to convert the mixture ofoxy-Michael products to the desired polycycle without isolation andrecycling of the undesired oxy-Michael product (Namba, K.; Jun, H.-S.;Kishi, Y. J. Am. Chem. Soc. 2004, 126, 7770. (b) Kaburagi, Y; Kishi, YOrg. Lett. 2007, 9, 723).

An experiment was set up to convert oxy-Michael products X-44 and X-45into polycycle X-46, thereby revealing that: (1) transformation of X-45into X-46 under the PPTS condition was cleaned facile, but (2)isomerization of X-44 to X-45 under the previously established basicconditions or ion-exchange-resin protocol was problematic; one problemidentified was the elimination of HCl to form iodo-diene (see the lowerhalf of FIG. 15). With this information, a reaction condition toestablish the equilibrium between two oxy-Michael products withoutelimination of HCl was searched for, and eventually found that theequilibration can be established with DBU or tetramethylguanidine inisopropanol or ethanol at room temperature, without the undesiredelimination. DBU, Triton B(OMe), and tetramethylguanidine were tested.DBU and tetramethylguanidine established an equilibrium in isopropanolor ethanol at RT without an elimination of HCl, whereas caused anelimination of HCl in DMF and MeCN. Triton B(OMe) caused unknowndecomposition of the oxy-Michael products.

Some of these conditions were translated to an ion-exchange resin baseddevice and found that polymer-bound guanidine base, coupled withpolymer-bound PPTS, was effective directly to convert a mixture ofoxy-Michael products X-44 and X-45 to polycycle X-46 in a high yieldwithout isolation/separation/equilibration (FIG. 16). Basic ion-exchangeresins tested included: Amberlite IRA-400, Amberlite IRA-402, AmberliteIRA-900, Amberlite A-21, Amberlite A-26, and Amberlite A-27. Acidicion-exchange resins tested included: Rexyn 101, Amberlite IR-120,Amberlite 15, and Amberlite IRC-86. Both purchased from Aldrich:polymer-bound guanidine: #358754; polymer-bound PPTS: #82817. As ethanolwas used as the solvent, an ester exchange was noticed if the reactionwas run over 1 day. However, it did not present an issue for preparativepurpose, as the conversion was usually complete within 12 hours. Thestructure of C1-C19 building block X-46 thus synthesized was fullysupported by spectroscopic data (HR-MS, ¹H and ¹³C NMR), which wasfurther confirmed by X-ray analysis of its derivative.

The synthesis reported is easy to scale; the overall yield of X-46 fromX-36 was 69% in a 11.4 g scale.

The C1-C19 building block X-46 of halichondrin Bs was synthesized via aselective activation/coupling of β-bromoenone X-34 with aldehyde X-35 ina Ni/Cr-mediated reaction. The first phase of study was a methoddevelopment to effect a coupling of a “naked” vinylogous anion with analdehyde. The study with the coupling of X-9+X-10→X-11 revealed: (1)β-bromoenone X-9b is a better nucleophile than the corresponding β-iodo-and β-chloroenones X-9a,c; (2) (Me)₂Phen(OMe)₂.NiCl₂ X-13b is a betterNi-catalyst than (Me)₂Phen(H)₂.NiCl₂ X-13a; (3) a low Ni-catalystloading, for example 0.05-0.01 mol % Ni-catalyst against 10 mol %Cr-catalyst, is crucial for an effective coupling. The second phase ofstudy was a method development to realize a selectiveactivation/coupling of poly-halogenated nucleophiles such as X-34. Thecompetition experiment of X-10+X-9b over X-10+X-31a-c revealed: (1)(Me)₂Phen(OMe)₂.NiCl₂ X-13b is more effective than (Me)₂Phen(H)₂.NiCl₂X-13a for the required selective activation/coupling; (2) a lowNi-catalyst loading, for example 0.05-0.01 mol % Ni-catalyst against 10mol % Cr-catalyst, can be important for discriminating β-bromoenone X-9bfrom the three types of vinyl iodides X-31a˜c. The third phase of studywas an application of the developed method to execute the proposedcoupling of X-34+X-35→X-36. For this application, a polyether-typeNi-catalyst X-37c, readily soluble in the reaction medium, wasintroduced to achieve the selective activation/coupling with higherefficiency. With use of ion-exchange-resin based device, the couplingproduct X-36 was transformed to the C1-C19 building block X-46 ofhalichondrin Bs without purification/separation of the intermediates.

Nucleophile X-34 are designed selectively to achieve specificbond-formation in a controlled manner, as illustrated in the synthesisof right-half of halichondrin A (FIG. 17).^(3c) Namely, C19 vinyl iodidewas used for the Ni/Cr-mediated coupling stereoselectively to form theC19-C20 bond, whereas C17 chloride allowed stereospecifically to formthe tetrahydrofuran ring in an S_(N)2 fashion.

Example 2. Unified Synthesis of C1-C19 Building Blocks of HalichondrinsVia Selective Activation/Coupling of Poly-Halogenated Nucleophiles in(Ni)/Cr-Mediated Reactions Synthesis Outlined in FIG. 21 Synthesis ofModel Halo-Acetylenic Ketones Y-18a-c

To a solution of trimethylsilyl acetylene (432 mg, 4.4 mmol) in THF (14mL) was added slowly n-BuLi (2.5 M in hexanes, 1.7 mL, 4.2 mmol) at −78°C. about 30 minutes. After 1 h, a solution of hexanal (400 mg, 4.0 mmol)in THF (6 mL) was added over another 30 min. The resulting mixture wasstirred at −78° C. for 2 h and then quenched by saturated NH₄Cl solution(10 mL) and extracted with EtOAc (15 mL×3). The extracts were washedwith brine (30 mL), dried over anhydrous MgSO₄, and then passed througha pad of silica gel (10 g). Elution with hexanes/EtOAc (10:1 to 4:1) andconcentration gave the crude product YS-1 as light yellow liquid. Thismaterial was immediately used for the next step without furtherpurification.

To a solution of propargyl alcohol YS-1 (800 mg, 4.0 mmol) in dryacetone (20 mL) was added silver nitrate AgNO₃ (135.9 mg, 0.80 mmol) andN-halosuccinimide (NIS: 1.50 g; NBS: 1.07 g; NCS: 801 mg; 6.0 mmol) atroom temperature. After being stirred at room temperature for 0.5 h(overnight for NCS case), the reaction mixture was diluted with Et₂O (40mL) and then quenched by 30 mL of 10% aqueous Na₂S₂O₃. The aqueous layerwas extracted with Et₂O (20 mL×3) and combined organic layer was washedwith brine, dried over anhydrous MgSO₄, and concentrated under vacuum.Purification of the residue by flash column chromatography on silica gelafforded halogenated propargyl alcohol YS-2 as colorless oil. Thematerial was immediately used for the next step without furtherpurification.

A solution of halogenated propargyl alcohol YS-2 (4.0 mmol) in CH₂Cl₂(40 mL) were added NaHCO₃ (3.36 g, 40 mmol) and Dess-Martin periodinane(2.54 g, 6.0 mmol) at room temperature and stirred for 1 h at roomtemperature. The reaction mixture was diluted with Et₂O (60 mL) and thenquenched with 10% Na₂S₂O₃ solution (60 mL), 40 mL of saturated NaHCO₃solution and vigorously stirred for 30 min. The aqueous phase wasextracted with Et₂O three times and the combined organic phases werewashed with 10% Na₂S₂O₃ (40 mL×2), saturated NaHCO₃ solution (40 mL),brine (40 mL) and dried over anhydrous MgSO₄. After removal of thesolvent, the crude material was purified by flash chromatography onshort silica gel column to give the halo-acetylenic ketones Y-18a-c asyellow oils.

Iodo-acetylenic ketone Y-18a:

67% yield; ¹H NMR (500 MHz, CDCl₃) δ: 2.53 (d, J=7.0 Hz, 2H), 1.65(quint, J=7.5 Hz, 2H), 1.38-1.22 (m, 4H), 0.88 (t, J=7.0 Hz, 3H); ¹³CNMR (125 MHz, CDCl₃) δ: 186.7, 95.0, 45.1, 31.0, 23.5, 22.3, 18.1, 13.8;IR(ATR) ν_(max): 2973, 2146, 1662, 1087, 1045, 639; HRMS (ESI) m/z:[M+H]⁺ calcd for C₈H₁₂IO, 250.9927; found, 250.9936.

Bromo-Acetylenic Ketone Y-18b:

61% yield; ¹H NMR (500 MHz, CDCl₃) δ: 2.54 (d, J=7.0 Hz, 2H), 1.65(quint, J=7.5 Hz, 2H), 1.38-1.22 (m, 4H), 0.88 (t, J=7.0 Hz, 3H); ¹³CNMR (125 MHz, CDCl₃) δ: 186.6, 79.9, 56.8, 45.3, 31.0, 23.5, 22.3, 13.8;IR(ATR) ν_(max): 2955, 2179, 1672, 1246, 1220, 687; HRMS (ESI) m/z:[M+H]⁺ calcd for C₈H₁₂BrO, 203.0072. found, 203.0076.

Chloro-Acetylenic Ketone Y-18c:

55% yield; ¹H NMR (500 MHz, CDCl₃) δ: 2.58 (d, J=7.0 Hz, 2H), 1.68(quint, J=7.5 Hz, 2H), 1.38-1.24 (m, 4H), 0.89 (t, J=7.5 Hz, 3H); ¹³CNMR (125 MHz, CDCl₃) δ: 187.6, 81.4, 78.2, 45.4, 31.0, 23.4, 22.3, 13.8;IR(ATR) ν_(max): 2954, 1815, 1731, 1462, 1230, 749; HRMS (ESI) m/z:[M+H]⁺ calcd for C₈H₁₂ClO, 159.0577. found, 159.0570.

Synthesis of Model Halo-Acetylenic Ketals Y-19a-c

To a solution of the above halo-acetylenic ketones Y-18a-c (1.5 mmol) inbenzene (30 mL) were added 1,3-propanediol (1.14 g, 15 mmol) andp-TsOH.H₂O (14.3 mg, 0.075 mmol) at room temperature and then refluxedfor 12 h with azeotropic removal of water using a Dean-Stark trap. Thereaction mixture was poured into saturated NaHCO₃ aq. solution,extracted with Et₂O and the extract was washed with brine, dried over byanhydrous MgSO₄. After removal of the solvent, the crude material waspurified by flash chromatography on short silica gel column to giveketals Y-19a-c as yellow oils.

Iodo-Acetylenic Ketal Y-19a:

83% yield; ¹H NMR (500 MHz, CDCl₃) δ: 4.20 (dt, J=13.0, 2.5 Hz, 2H),3.88 (dd, J=11.5, 5.0 Hz, 2H), 2.09-1.96 (m, 1H), 1.79-1.74 (m, 2H),1.53-1.44 (m, 2H), 1.39-1.22 (m, 5H), 0.88 (t, J=7.0 Hz, 3H); ¹³C NMR(125 MHz, CDCl₃) δ: 97.4, 91.6, 62.5, 41.8, 31.6, 25.1, 22.9, 22.5,14.0, 4.3; HRMS (ESI) m/z: [M+Na]⁺ calcd for C₁₁H₁₇INaO₂, 331.0165.found, 331.0162.

Bromo-Acetylenic Ketal Y-19b:

85% yield; ¹H NMR (500 MHz, CDCl₃) δ: 4.18 (dt, J=12.0, 3.0 Hz, 2H),3.87 (dd, J=12.0, 5.5 Hz, 2H), 2.08-1.95 (m, 1H), 1.79-1.72 (m, 2H),1.52-1.44 (m, 2H), 1.37-1.23 (m, 5H), 0.87 (t, J=7.5 Hz, 3H); ¹³C NMR(125 MHz, CDCl₃) δ: 97.1, 76.9, 62.4, 47.1, 41.8, 31.6, 25.1, 22.8,22.5, 14.0; HRMS (ESI) m/z: [M+H]⁺ calcd for C₁₁H₈BrO₂, 261.0490. found,261.0483.

Chloro-Acetylenic Ketal Y-19c:

60% yield; ¹H NMR (500 MHz, CDCl₃) δ: 4.24 (dt, J=12.5, 2.5 Hz, 2H),3.88 (dd, J=12.5, 5.5 Hz, 2H), 2.09-1.98 (m, 1H), 1.80-1.75 (m, 2H),1.56-1.48 (m, 2H), 1.37-1.23 (m, 5H), 0.88 (t, J=7.0 Hz, 3H); ¹³C NMR(125 MHz, CDCl₃) δ: 96.2, 79.6, 75.0, 62.3, 41.8, 31.8, 25.2, 22.8,22.5, 14.0; HRMS (ESI) m/z: [M+H]⁺ calcd for C₁₁H₁₈ClO₂, 217.0995.found, 217.0998.

General Procedure of Catalytic, Asymmetric (Ni)/Cr-Mediated Couplingwith Halo-Acetylenic Ketones Y-18a-c and Halo-Acetylenic Ketals Y-19a-c

Synthesis of (S)-Y-21, a, and b is available from Liu, X.; Li, X.; Chen,Y.; Hu, Y.; Kishi, Y. J. Am. Chem. Soc. 2012, 134, 6136. Ni-catalystY-22 was synthesized with the following procedure.

To a stirred solution of 1,10-phenanthroline anhydrous (5.0 g, 27.7mmol) in toluene (200 mL) and THF (25 mL) was added 0.7M i-PrLi inpentane solution (24 mL, 84 mmol) dropwise at room temperature. Afterstirring for 16 h at room temperature, the mixture was added H₂O (100mL). The separated aqueous layer was extracted with CH₂Cl₂ (50 mL×3) andthe combined organic layer was treated with MnO₂ (20 g, 230 mmol) atroom temperature. After stirring for 2 h, the mixture was added MgSO₄(20 g) and stirred for 15 min. The mixture was filtered through Celiteand the filtrate was concentrated. The crude mixture was purified bySiO₂ flash column chromatography (hexanes/EtOAc=9:1) to provide(i-Pr)₂Phen(H)₂ Y-22′(6.3 g, 23.8 mmol, 86%) (Metallinos, C.; Barrett,F. B.; Wang, Y.; Xu, S. F.; Taylor, N. J. Tetrahedron 2006, 62, 11145).

Y-22′:

¹H NMR (500 MHz, CDCl₃) δ 1.48 (d, J=7.0 Hz, 12H), 1.94 (hept, J=7.0 Hz,2H), 7.55 (d, J=8.0 Hz, 2H), 7.68 (s, 2H), 8.14 (d, J=8.0 Hz, 2H); ¹³CNMR (125 MHz, CDCl₃) δ 22.9, 37.3, 120.1, 125.4, 127.2, 136.4, 145.2,167.8; HRMS (ESI) m/z: [M+Na]⁺ calcd for C₁₈H₂₀N₂Na, 287.1524. found,287.1527.

To a stirred solution of (i-Pr)₂Phen(H)₂ Y-22′ (6.3 g, 23.8 mmol) inEtOH (100 mL) and triethyl room temperature formate (3 mL) was added asolution of NiCl₂.6H₂O (17 g, 71.5 mmol) in EtOH (100 mL) dropwise atroom temperature. After stirring for overnight at room temperature, theprecipitate was filtered and the resulting solid was washed Et₂O. Thispurple solid was dissolved into CH₃CN and the mixture was refluxed underN₂ atmosphere. Then this solution was cooled to room temperature, togive purple crystals. The crystals were filtered and washed with Et₂Oand dried under reduced pressure for overnight to provide Y-22 (4.5 g,11.4 mmol, 48%) as purple shiny crystal.

General Procedure of Asymmetric Catalytic Ni/Cr-Mediated Coupling.

Cr-Catalyst Preparation:

To a mixture of natural sulfonamide (Guo, H.; Dong, C. G.; Kim, D. S.;Urabe, D.; Wang, J.; Kim, J. T.; Liu, X.; Sasaki, T.; Kishi, Y. J. Am.Chem. Soc. 2009, 131, 15387) (S)-Y-21 (3.44 mg, 11.0 μmol), protonsponge (Aldrich, purified by sublimation; 2.36 mg, 11.0 μmol) and CrCl₂(Aldrich, 99.99% mg, 1.23 mg, 10.0 μmol) was added MeCN (Baker, ultralow water; 50 μL) in a glovebox. The mixture was stirred for 60 min atroom temperature under nitrogen.

Coupling:

To a separate vial were added ZrCp₂Cl₂ (Aldrich, 98%; 43.8 mg, 0.15mmol), Mn powder (Aldrich, 99.99%, powder; 11.0 mg, 0.20 mmol), LiCl(Aldrich, anhydrous, grinded; 8.5 mg, 0.20 mmol), NiCl₂. complex Y-22 ori or ii (0.05 mol %) or no NiCl₂. catalyst, aldehyde Y-20 (32.7 mg, 0.10mmol) and halo-acetylenic ketones Y-18a-c or halo-acetylenic ketalsY-19a-c (0.17 mmol). The deep green Cr-catalyst in the first vial wastransferred to the second reaction vial with syringe under nitrogen. Thereaction mixture was stirred under nitrogen until the reaction wascompleted (˜3 hr, TLC monitor), and diluted with EtOAc (2.0 mL).Florisil (ca. 50 mg) was added, and the mixture was stirred for 30 min,filtered through a short silica gel pad with 1:1 hexanes/EtOAc. Theeluent was concentrated in vacuo to furnish the crude coupling product,which was purified by preparative TLC (hexanes/EtOAc=4:1) to give YS-3as yellow liquid or YS-4 as colorless oil.

The isolated yield for coupling reactions with Ni-catalysts Y-22 or i orii and no added Ni-catalyst are summarized below (Table 2).

TABLE 2 Results                   Isolated yield          

         

         

Y-22 11% 49% 20% 82% 93%   8% i 15% 48% 18% 81% 94% <5% ii  8% 26% 10%79% 90%   6% no Ni 18% 50% 22% 85% 97%   9%

Coupling Product YS-3:

¹H NMR (500 MHz, CDCl₃) δ: 7.70-7.61 (m, 4H), 7.47-7.32 (m, 6H), 4.62(q, J=6.0 Hz, 1H), 3.78-3.58 (m, 2H), 3.28 (d, J=6.0 Hz, 1H), 2.55 (t,J=7.5 Hz, 1H), 2.00-1.90 (m, 1H), 1.89-1.79 (m, 1H), 1.77-1.62 (m, 3H),1.37-1.24 (m, 4H), 1.06 (s, 9H), 1.05-1.02 (m, 2H), 0.89 (s, 3H); ¹³CNMR (125 MHz, CDCl₃) δ: 187.9, 135.6, 133.1, 129.8, 127.8, 92.0, 83.6,63.9, 62.0, 45.4, 34.6, 31.1, 28.1, 26.8, 23.6, 22.4, 19.1, 13.9;IR(ATR) ν_(max): 2930, 1676, 1427, 1111, 823, 701, 505; HRMS (ESI) m/z:[M+K]⁺ calcd for C₂₈H₃₈KO₃Si, 489.2222. found, 489.2224.

Coupling Product YS-4:

1H NMR (500 MHz, CDCl₃) δ: 7.71-7.68 (m, 4H), 7.46-7.42 (m, 2H),7.41-7.37 (m, 4H), 4.58 (q, J=6.0 Hz, 1H), 4.27-4.20 (m, 2H), 3.90-3.85(m, 2H), 3.77-3.67 (m, 2H), 2.82 (d, J=6.0 Hz, 1H), 2.09-1.98 (m, 1H),1.97-1.83 (m, 3H), 1.82-1.71 (m, 3H), 1.57-1.49 (m, 2H), 1.34-1.26 (m,5H), 1.06 (s, 9H), 0.88 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ: 135.5,133.4, 129.7, 127.7, 96.5, 88.1, 80.6, 63.8, 62.3, 62.1, 41.9, 35.1,31.7, 28.2, 26.8, 25.3, 23.0, 22.5, 19.1, 14.0; HRMS (ESI) m/z: [M+K]⁺calcd for C₃₁H₄₄KO₄Si, 547.2640. found, 547.2637.

Synthesis Outlined in FIG. 22 Synthesis of C12-C19 Vinyl Bromide Y-24a

For the preparation of Y-23a ((a) Liu, S.; Kim, J. T.; Dong, C. G.;Kishi, Y. Org. Lett. 2009, 11, 4520, (b) Ueda, A.; Yamamoto, A.; Kato,D.; Kishi, Y. J. Am. Chem. Soc. 2014, 136, 5171).

To a solution of trimethylsilyl acetylene (4.93 g, 50 mmol) in THF (50mL) was added slowly n-BuLi (2.5 M in hexanes, 14.56 mL, 53 mmol) at−78° C. After 1 h, a solution of BF₃.Et₂O (4.66 mL, 54 mmol) in THF (10mL) was added over 30 min using syringe pump and the mixture was stirredat −78° C. for 1 h. Then a solution of aldehyde Y-23a (18 mmol) in THF(15 mL) was added over 10 min. After stirring at −78° C. for 3 h, theresulting mixture was poured into a saturated NaHCO₃ solution at 0° C.The aqueous layer was extracted with EtOAc three times and the combinedorganic layer was washed with brine, dried over anhydrous Na₂SO₄, andconcentrated under vacuum. Purification of the residue by flash columnchromatography on silica gel afforded propargylic alcohol YS-5 (3.21 g,90%) as a colorless oil.

Propargylic Alcohol YS-5:

¹H NMR (500 MHz, C₆D₆) δ: 5.27 (s, 1H), 5.23 (s, 1H), 4.10-4.05 (m, 2H),2.42 (dd, J=15.0, 3.5 Hz, 1H), 2.42 (dd, J=15.0, 5.0 Hz, 1H), 1.84-1.55(m, 4H), 0.17 (s, 9H); ¹³C NMR (125 MHz, C₆D₆) δ: 129.7, 119.9, 107.4,89.3, 62.1, 59.6, 49.9, 34.5, 33.2, −0.07; HRMS (ESI) m/z: [M+H]⁺ calcdfor C₁₂H₂₀BrClNaOSi, 345.0053; found, 345.0059.

To a solution of propargyl alcohol YS-5 (998 mg, 3.1 mmol) in dryacetone (12 mL) was added silver nitrate (105 mg, 0.62 mmol) andN-bromosuccinimide (822 mg, 4.6 mmol) at room temperature. The reactionvessel was wrapped by aluminum foil to avoid light. After being stirredat room temperature for 0.5 h, the reaction mixture was cooled to 0° C.and then quenched by water. Then the solution was extracted with etherand the combined organic layer was washed with 10% aqueous Na₂S₂O₃ andbrine, dried over anhydrous Na₂SO₄, and concentrated under vacuum.Purification of the residue by flash column chromatography on silica gelafforded bromo-propargyl alcohol YS-6 as a colorless oil. This materialwas immediately used for the next step without further purification.

Bromo-Propargylic Alcohol YS-6:

¹H NMR (500 MHz, C₆D₆) δ: 5.27 (s, 1H), 5.23 (s, 1H), 4.02-3.96 (m, 1H),3.94-3.84 (m, 1H), 2.36 (dd, J=15.0, 3.5 Hz, 1H), 2.26 (dd, J=15.0, 3.5Hz, 1H), 1.72-1.42 (m, 4H); ¹³C NMR (125 MHz, C₆D₆) δ: 129.7, 120.0,81.5, 62.5, 59.5, 49.9, 45.3, 34.3, 33.0; HRMS (ESI) m/z: [M+H]⁺ calcdfor C₉H₁₂Br₂ClO, 328.8943; found, 328.8938.

To a solution of the above propargylic alcohol YS-6 in CH₂Cl₂ (15 mL)were added NaHCO₃ (2.6 g, 31 mmol) and Dess-Martin periodinane (2.0 g,4.6 mmol) at room temperature and stirred for 0.5 h at room temperature.The reaction mixture was quenched with 10% Na₂S₂O₃ and saturated NaHCO₃solution and vigorously stirred for 30 min. The aqueous phase wasextracted with CH₂Cl₂ three times and the combined organic phases werewashed with 10% Na₂S₂O₃ and saturated NaHCO₃ solution and then driedover anhydrous Na2SO₄. After removal of solvent, the crude material waspurified by flash chromatography on short silica gel column to giveynone YS-7 as colorless oil. This material was immediately used for thenext step without further purification.

Acetylenic Ketone YS-7:

[α]_(D) ²⁰=+13.5 (c 1.0, CHCl₃); ¹H NMR (500 MHz, C₆D₆) δ: 5.24 (s, 1H),5.19 (s, 1H), 3.91-3.85 (m, 1H), 2.32 (ddd, J=18.0, 9.0, 5.0 Hz, 1H),2.29 (dd, J=14.5, 8.5 Hz, 1H), 2.18 (dd, J=15.0, 5.5 Hz, 1H), 2.13 (ddd,J=18.5, 9.5, 6.5 Hz, 1H), 1.70-1.62 (m, 1H), 1.52-1.44 (m, 1H); ¹³C NMR(125 MHz, C₆D₆) δ: 183.5, 129.3, 120.1, 80.3, 58.8, 56.7, 49.8, 42.2,31.0; IR(ATR) ν_(max): 3019, 1677, 1214, 749, 668; HRMS (ESI) m/z:[M+Na]⁺ calcd for C₉H₉Br₂ClNaO, 348.8606. found, 348.8600.

To a solution of the above ynone YS-7 (3.1 mmol) in benzene (62 mL) wereadded 1,3-propanediol (2.4 g, 31.0 mmol) and p-TsOH.H₂O (29.3 mg, 0.16mmol) at room temperature and then refluxed for 12 h with azetropicremoval of water using a Dean-Stark trap. The reaction mixture waspoured into saturated NaHCO₃ aq. solution, extracted with EtOAc and theextract was washed with brine, dried over sodium sulfate. After removalof the solvent, the crude material was purified by flash chromatographyon short silica gel column to give the ketal derivative Y-24a (976 mg,82% in three steps) as colorless oil.

Ketal Y-24a:

[α]²⁰ _(D)+6.6 (c 0.92, CHCl₃); ¹H NMR (600 MHz, C₆D₆) δ: 5.22-5.21 (m,1H), 5.17-5.16 (m, 1H), 4.13 (tdd, J=8.7, 5.2, 3.5 Hz, 1H), 3.88-3.84(m, 2H), 3.48 (ddd, J=12.0, 5.1, 1.2 Hz, 2H), 2.37 (dd, J=14.8, 8.5 Hz,1H), 2.33-2.29 (m, 1H), 2.26-2.21 (m, 1H), 2.07-2.01 (m, 2H), 1.93-1.87(m, 1H), 1.60 (dddt, J=18.1, 13.6, 7.8, 5.2 Hz, 1H), 0.55-0.52 (m, 1H);¹³C NMR (125 MHz, C₆D₆) δ: 129.8, 119.8, 96.8, 77.8, 62.4, 59.6, 49.8,47.5, 38.9, 31.6, 25.2; HRMS (ESI) m/z: [M+Na]⁺ calcd forC₁₂H₁₅Br₂ClO₂Na, 406.9025; found, 406.9029.

Synthesis of C12-C19 Vinyl Iodide Y-24b

To a solution of trimethylsilyl acetylene (1.0 g, 10.2 mmol) in THF (10mL) was added slowly n-BuLi (2.5 M in hexanes, 4.1 mL, 10.2 mmol) at−78° C. After 1 h, a solution of BF₃.Et₂O (1.4 mL, 11.0 mmol) in THF(2.5 mL) was added over 30 min using syringe pump and the mixture wasstirred at −78° C. for 1 h (Yamauchi, M.; Hirao, I. Tetrahedron Lett.1983, 24, 391). Then a solution of aldehyde Y-23b (1.0 g, 3.6 mmol) inTHF (2.5 mL) was added over 30 min. After stirring at −78° C. for 3 h,the resulting mixture was poured into a saturated NaHCO₃ solution at 0°C. The aqueous layer was extracted with EtOAc three times and thecombined organic layers were washed with brine, dried over Na₂SO₄, andconcentrated under vacuum. Purification of the residue by flash columnchromatography on silica gel afforded propargylic alcohol YS-8 (1.15 g,80%) as a colorless oil.

Propargylic Alcohol YS-8:

¹H NMR (500 MHz, CDCl₃) δ: 6.18 (s, 1H), 5.85 (s, 1H), 4.42 (d, J=6.0Hz, 1H), 4.24-4.12 (m, 1H), 2.77 (d, J=7.0 Hz, 2H), 2.12-1.94 (m, 2H),1.90-1.74 (m, 2H), 0.17 (s, 9H); ¹³C NMR (125 MHz, CDCl₃) δ: 128.9,106.0, 105.9, 90.1, 62.1, 60.5, 53.4, 34.3, 32.6, −0.16; HRMS (ESI) m/z:[M+H]⁺ calcd for C₁₂H₂₁ClIOSi, 371.0095. found, 371.0103.

To a solution of the above trimethylsilyl acetylene YS-8 (1.10 g, 3.0mmol) in dry acetone (15 mL) was added silver nitrate AgNO₃ (103 mg,0.60 mmol) and NBS (806 mg, 4.5 mmol) at room temperature. The reactionvessel was wrapped by aluminum foil to avoid light. After being stirredat room temperature for 0.5 h, the reaction mixture was cooled to 0° C.and then quenched by water. Then the solution was extracted with etherand the combined organic layer was washed with 10% aqueous Na₂S₂O₃ andbrine, dried over Na₂SO₄, and concentrated under vacuum. Purification ofthe residue by flash column chromatography on silica gel affordedbromoacetylene YS-9 as a colorless oil. This material was immediatelyused for the next step without further purification.

Bromoacetylene YS-9:

¹H NMR (500 MHz, CDCl₃) δ: 6.18 (s, 1H), 5.86 (s, 1H), 4.47 (q, J=7.5Hz, 1H), 4.22-4.12 (m, 1H), 2.77 (d, J=7.5 Hz, 2H), 2.08-1.96 (m, 2H),1.94-1.79 (m, 2H); ¹³C NMR (125 MHz, CDCl₃) δ: 129.0, 105.8, 80.4, 62.7,60.5, 53.4, 45.9, 34.3, 32.6; HRMS (ESI) m/z: [M+H]⁺ calcd forC₉H₁₂BrClIO, 376.8805. found, 376.8811.

A solution of the above propargylic alcohol YS-9 (3.0 mmol) in CH₂Cl₂(15 mL) were added NaHCO₃ (2.5 g, 30.0 mmol) and Dess-Martin periodinane(1.9 g, 4.5 mmol) at room temperature and stirred for 0.5 h at roomtemperature. The reaction mixture was quenched with 10% Na₂S₂O₃ solutionand saturated NaHCO₃ solution and vigorously stirred for 30 min. Theaqueous phase was extracted with CH₂Cl₂ three times and the combinedorganic phase was washed with 10% Na₂S₂O₃ solution and saturated NaHCO₃solution and then dried over anhydrous Na₂SO₄. After removal of solvent,the crude material was purified by flash chromatography on short silicagel column to give the ynone YS-10 as colorless oil. This material wasimmediately used for the next step without further purification.

Bromo-Acetylenic Ketone YS-10:

[α]_(D) ²⁰=+10.4 (c 1.0, CHCl₃); ¹H NMR (500 MHz, C₆D₆) δ: 5.65 (s, 1H),5.53 (s, 1H), 3.87-3.81 (m, 1H), 2.32 (ddd, J=18.0, 9.0, 5.0 Hz, 1H),2.24 (dd, J=14.5, 9.0 Hz, 1H), 2.18 (dd, J=15.5, 5.5 Hz, 1H), 2.13 (ddd,J=18.0, 8.5, 6.5 Hz, 1H), 1.69-1.61 (m, 1H), 1.53-1.45 (m, 1H); ¹³C NMR(125 MHz, C₆D₆) δ: 183.5, 129.0, 105.9, 80.3, 60.0, 56.7, 53.3, 42.2,30.8; IR(ATR) ν_(max): 2900, 2158, 1672, 1614, 1109, 899, 752; HRMS(ESI) m/z: [M+Na]⁺ calcd for C₉H₉BrClINaO, 396.8468. found, 396.8459.

To a solution of the above acetylenic ketone YS-10 (3.0 mmol) in benzene(60 mL) were added 1,3-propanediol (2.3 g, 30.0 mmol) and p-TsOH.H₂O(28.5 mg, 0.15 mmol) at room temperature and then refluxed for 12 h withazetropic removal of water using a Dean-Stark trap. The reaction mixturewas poured into saturated NaHCO₃ aq. solution, extracted with EtOAc andthe extract was washed with brine, dried over sodium sulfate. Afterremoval of the solvent, the crude material was purified by flashchromatography on short silica gel column to give the ketal Y24b (956mg, 73% in three steps) as colorless oil.

Ketal Y24b:

[α]_(D) ²⁰=+5.6 (c 1.0, CHCl₃); ¹H NMR (500 MHz, C₆D₆) δ: 5.66 (s, 1H),5.51 (s, 1H), 4.12-4.06 (m, 1H), 3.87 (td, J=12.4, 2.3 Hz, 2H),3.52-3.48 (m, 2H), 2.33 (d, J=6.4 Hz, 2H), 2.21-2.15 (m, 1H), 2.05-1.97(m, 2H), 1.91-1.84 (m, 1H), 1.67-1.58 (m, 1H), 0.60 (ddq, J=12.1, 2.6,1.3 Hz, 1H); ¹³C NMR (125 MHz, C₆D₆) δ: 128.6, 106.5, 96.7, 77.7, 62.4,60.8, 53.2, 47.5, 38.8, 31.4, 25.1; HRMS (ESI) m/z: [M+Na]⁺ calcd forC₁₂H₁₅BrClIO₂Na, 454.8886. found, 454.8892.

Synthesis Outlined in FIG. 24 Synthesis of Y-27a Via (Ni)/Cr-MediatedCoupling of Y-11 and Y-24a

To a mixture of CrCl₂ (49.2 mg, 0.4 mmol), (R)-Y-21 ((a) Choi, H.;Demeke, D.; Kang, F.-A.; Kishi, Y.; Nakajima, K.; Nowak, P.; Wan, Z.-K.;Xie, C. Pure Appl. Chem. 2003, 75, 1, (b) Reference 3) (137 mg, 0.44mmol), and proton sponge (94.3 mg, 0.44 mmol) in a glove box was addedEtCN (5.0 mL, 0.4 M) and stirred for 1 h at room temperature. In aseparate flask, bromo-acetylene Y-24a (1.35 g, 3.5 mmol), aldehyde Y-11(1.0 g, 2.0 mmol), LiCl (339.1 mg, 8.0 mmol), Mn (439.5 mg, 8.0 mmol)were mixed together and the Cr-complex solution was transferred to theflask. Then TES-Cl (0.84 mL, 5.0 mmol) was added into the reactionmixture. After stirring for 6 h at room temperature, the reaction wasremoved from the glove box and diluted with anhydrous Et₂O. Sat. aq.NaHCO₃, followed by potassium serinate solution, was added carefully toquench the reaction and the corresponding mixture was stirred vigorouslyfor 30 min. The resultant mixture was filtered through short pad ofsilica gel and concentrated. The crude material was purified by flashchromatography on silica gel to give TES-protected alcohol YS-11 (1.70g, 92% yield).

The fractions eluded with 1:10 EtOAc/hexanes were combined and purifiedwith silica gel column chromatography (1:10 EtOAc/hexanes) to givereduced bromoacetylene YS-12 (˜400 mg, ˜38%) and a fraction containinghomo-dimer YS-13. This faction was further purified with preparative TLC(1:10 EtOAc/hexanes), to give homo-dimer YS-13 (5.9 mg, 0.3%).

Coupling product YS-11:

[α]²⁰ _(D) −22.3 (c 1.0, CHCl₃); ¹H NMR (600 MHz, C₆D₆) δ: 5.70 (d,J=4.4 Hz, 1H), 5.27 (s, 1H), 5.28-5.26 (d, J=9.5 Hz, 1H), 4.37-4.24 (m,4H), 4.14-4.12 (m, 1H), 4.09-4.07 (m, 1H), 4.03 (tt, J=10.1, 5.0 Hz,1H), 3.85 (dt, J=6.4, 3.1 Hz, 1H), 3.79-3.74 (m, 1H), 3.67 (ddd, J=16.3,11.3, 5.0 Hz, 2H), 3.34-3.33 (m, 3H), 2.86 (dd, J=9.5, 2.2 Hz, 1H),2.53-2.51 (m, 2H), 2.45-2.38 (m, 3H), 2.28-2.21 (m, 2H), 2.18-2.13 (m,1H), 2.10 (dd, J=15.1, 5.0 Hz, 1H), 1.85-1.74 (m, 1H), 1.49-1.43 (m,1H), 1.42-1.32 (m, 1H), 1.25-1.17 (m, 1H), 1.12 (t, J=7.9 Hz, 9H),1.09-1.08 (s, 9H), 0.87 (m, 6H), 0.27 (s, 3H), 0.25 (s, 3H), 0.07 (s,3H), 0.06 (s, 3H); ¹³C NMR (125 MHz, C₆D₆) δ: 170.5, 129.6, 119.5, 96.1,86.0, 83.2, 81.0, 78.9, 74.12, 72.7, 70.3, 64.5, 63.4, 62.2, 62.0, 59.8,50.8, 49.8, 40.5, 39.0, 31.7, 30.6, 28.9, 26.3, 26.1, 25.3, 18.8, 18.5,7.2, 5.6, −4.3, −4.5, −4.7, −5.1; HRMS (ESI) m/z: [M+H]⁺ calcd forC₄₂H₇₇BrClO₉Si₃, 923.3742. found, 923.3705.

Reduced Bromoacetylene YS-12:

[α]²⁰ _(D) +6.9 (c 1.0, CHCl₃); ¹H NMR (500 MHz, C₆D₆) δ: 5.24 (d, J=2.0Hz, 1H), 5.21 (d, J=1.5 Hz, 1H), 4.24-4.18 (m, 1H), 4.12 (t, J=13.0 Hz,2H), 3.58 (dd, J=12.0, 6.0 Hz, 2H), 2.44 (dd, J=14.0, 8.0 Hz, 1H), 2.39(dd, J=13.5, 5.5 Hz, 1H), 2.36-2.29 (m, 1H), 2.18-2.10 (m, 2H), 2.09 (s,1H), 2.05-1.97 (m, 1H), 1.74-1.65 (m, 1H), 0.64 (d, J=13.0 Hz, 1H); ¹³CNMR (125 MHz, C₆D₆) δ: 129.6, 119.6, 95.7, 79.8, 74.8, 62.0, 59.5, 49.6,38.7, 31.5, 25.1; HRMS (ESI) m/z: [M+Na]⁺ calcd for C₁₂H₁₆BrClNaO₂,218.9914. found, 328.9910.

Homo-Dimer YS-13:

[α]²⁰ _(D) +6.8 (c 1.0, CHCl₃); ¹H NMR (500 MHz, C₆D₆) δ: 5.26 (d, J=2.0Hz, 1H), 5.22 (d, J=1.0 Hz, 1H), 4.21-4.15 (m, 1H), 4.12 (dt, J=12.0,3.0 Hz, 2H), 3.58-3.54 (m, 2H), 2.45-2.33 (m, 3H), 2.18-2.10 (m, 2H),2.04-1.95 (m, 1H), 1.71-1.60 (m, 1H), 0.60 (d, J=12.5 Hz, 1H); ¹³C NMR(125 MHz, C₆D₆) δ: 129.8, 119.9, 96.6, 77.6, 70.6, 62.8, 59.7, 49.9,39.1, 31.7, 25.1; HRMS (ESI) m/z: [M+H]⁺ calcd for C₂₄H₃₁Br₂Cl₂O₄,610.9906. found, 610.9904.

To a solution of TES-protected alcohol YS-11 (25.5 mg, 27.6 μmol) inCH₂Cl₂ (89 μL) was added co-solvent mixture TFA/H₂O/CH₂Cl₂ (4:1:10)(42.3 μL) at 0° C. The reaction mixture was stirred vigorously at roomtemperature until TLC showed a complete disappearance of the startingmaterial (around 0.5 h). The reaction was diluted with EtOAc, quenchedcarefully with sat. NaHCO₃ aq., and the organic phases were separatedand the aqueous phase was extracted with EtOAc three times, washed withbrine. The combined organic phases were dried over Na₂SO₄ andconcentrated. The crude material was flushed through a short silica gelcolumn to afford acetylenic ketone Y-27a (16.1 mg, 78%) as colorlessoil.

Coupling Product Y-27a:

[α]²⁰ _(D) −52.3 (c 1.0, CHCl₃); ¹H NMR (600 MHz, C₆D₆) δ: 6.15 (d,J=9.4 Hz, 1H), 5.21 (s, 1H), 5.16 (s, 1H), 4.11 (s, 1H), 4.08-4.06 (m,2H), 3.88-3.84 (m, 2H), 3.73-3.67 (m, 2H), 3.33 (s, 3H), 2.79 (dd,J=9.5, 2.2 Hz, 1H), 2.48 (ddt, J=17.8, 9.0, 4.3 Hz, 1H), 2.38-2.28 (m,2H), 2.23 (dd, J=14.9, 8.8 Hz, 1H), 2.16 (dd, J=14.9, 5.0 Hz, 1H), 0.02(m, 2H), 1.72 (m, 1H), 1.56 (dtd, J=14.4, 9.5, 5.0 Hz, 1H), 1.39-1.19(m, 3H), 1.03 (s, 9H), 0.80 (s, 9H), 0.16 (m, 6H), −0.11 (s, 3H), −0.12(s, 3H); ¹³C NMR (125 MHz, C₆D₆) δ: 182.4, 168.0, 126.8, 117.2, 88.8,81.8, 76.8, 72.9, 71.9, 70.45, 70.3, 62.6, 61.4, 56.2, 48.4, 47.0, 39.6,37.9, 28.6, 27.7, 27.4, 26.8, 23.5, 23.3, 16.0, 15.6, −6.5, −7.4. IR(ATR) ν_(max): 3018, 1733, 1675, 1214, 1073, 751; HRMS (ESI) m/z:[M+Na]⁺ calcd for C₃₃H₅₆BrClO₈Si₂Na, 773.2283. found, 773.2285.

On treatment with TBS protection (TBS-Cl, imidazole, CH₂Cl₂), couplingproduct Y-27a furnished the acetylenic ketone previously synthesizedwith use of two (Ni)/Cr-mediated coupling reactions (Ueda, A.; Yamamoto,A.; Kato, D.; Kishi, Y. J. Am. Chem. Soc. 2014, 136, 5171).

Synthesis of Y-27b Via (Ni)/Cr-Mediated Coupling of Y-11 and Y-24b

To a mixture of CrCl₂ (16.4 mg, 0.13 mmol), (R)-Y-21 (Choi, H.; Demeke,D.; Kang, F.-A.; Kishi, Y.; Nakajima, K.; Nowak, P.; Wan, Z.-K.; Xic, C.Pure Appl. Chem. 2003, 75, 1) (41.6 mg, 0.15 mmol), and proton sponge(32.1 mg, 0.15 mmol) in a glove box was added EtCN (1.5 mL) and stirredfor 1 h at room temperature. In a separate flask, bromo-acetylene Y-27b(441 mg, 1.0 mmol), aldehyde Y-11 (305 mg, 0.61 mmol), LiCl (103 mg, 2.5mmol), Mn (133 mg, 2.5 mmol) were mixed together and the Cr-complexsolution was transferred to the flask. Then TES-Cl (254 μL, 1.5 mmol)was added into the reaction mixture. After stirring for 6 h at roomtemperature, the reaction was removed from the glove box and dilutedwith anhydrous Et₂O. Sat. aq. NaHCO₃, followed by potassium serinatesolution, was added carefully to quench the reaction and thecorresponding mixture was stirred vigorously for 30 min. The resultantmixture was filtered through short pad of silica gel and concentrated.The crude material was purified by flash chromatography on silica gel togive TES-protected alcohol YS-14 (529 mg, 89%).

The fractions eluded with 1:10 EtOAc/hexanes were combined and purifiedwith silica gel column chromatography (1:10 EtOAc/hexanes) to givereduced bromoacetylene YS-15 (˜100 mg, ˜28%) and a fraction containinghomo-dimer YS-16. This faction was further purified with preparative TLC(1:10 EtOAc/hexanes), to give homo-dimer YS-16 (2.6 mg, 0.4%).

Coupling Product YS-14:

[α]²⁰ _(D) −29.4 (c 0.98, CHCl₃); ¹H NMR (500 MHz, C₆D₆) δ: 5.78 (m,1H), 5.74 (d, J=4.3 Hz, 1H), 5.59 (m, 1H), 4.40-4.25 (m, 3H), 4.16 (m,1H), 4.12 (dd, J=6.4, 4.4 Hz, 1H), 4.07 (td, J=10.2, 4.2 Hz, 1H),3.91-3.86 (m, 1H), 3.80 (ddd, J=10.9, 8.0, 5.3 Hz, 1H), 3.74-3.69 (m,2H), 3.39 (s, 3H), 2.89 (dd, J=9.5, 2.0 Hz, 1H), 2.57 (dd, J=14.8, 4.9Hz, 1H), 2.52-2.44 (m, 3H), 2.35-2.11 (m, 5H), 1.82 (dddt, J=17.3, 12.8,8.4, 4.5 Hz, 1H), 1.50-1.46 (m, 1H), 1.14-1.35 (m, 1H), 1.30-1.19 (m,2H), 1.19 (t, J=7.9 Hz, 9H), 1.12 (s, 9H), 0.91 (s, 9H), 0.91 (m, 6H),0.27 (s, 3H), 0.25 (s, 3H), 0.07 (s, 3H), 0.06 (s, 3H); ¹³C NMR (125MHz, C₆D₆) δ: 170.9, 128.7, 106.8, 96.4, 86.3, 83.6, 81.3, 80.5, 79.3,74.5, 73.1, 70.6, 64.9, 63.8, 62.6, 62.4, 61.3, 53.5, 51.1, 40.9, 39.4,31.9, 30.9, 29.3, 26.6, 26.5, 25.6, 7.5, 5.9, −4.0, −4.1, −4.3, −4.7.HRMS (ESI) m/z: [M+Na]⁺ calcd for C₄₂H₇₆ClIO₉Si₃Na, 993.3428. found,993.3429.

Reduced Bromoacetylene YS-15:

[α]²⁰ _(D) +6.0 (c 1.0, CHCl₃); ¹H NMR (500 MHz, C₆D₆) δ: 5.67 (d, J=1.0Hz, 1H), 5.53 (d, J=1.5 Hz, 1H), 4.21-4.15 (m, 1H), 4.02 (dt, J=13.0,2.5 Hz, 2H), 3.58 (dd, J=12.0, 6.0 Hz, 2H), 2.38 (dd, J=6.5, 1.0 Hz,2H), 2.34-2.27 (m, 1H), 2.17-2.11 (m, 2H), 2.10 (s, 1H), 2.05-1.97 (m,1H), 1.76-1.64 (m, 1H), 0.64 (d, J=13.0 Hz, 1H); ¹³C NMR (125 MHz, C₆D₆)δ: 128.4, 106.3, 95.6, 79.8, 74.8, 62.0, 60.7, 53.0, 38.6, 31.3, 25.0;HRMS (ESI) m/z: [M+Na]⁺ calcd for C₁₂H₁₆ClINaO₂, 376.9781; found,376.9780.

Homo-Coupling Product YS-16:

[α]²⁰ _(D) +5.9 (c 1.0, CHCl₃); ¹H NMR (500 MHz, C₆D₆) δ: 5.67 (d, J=1.5Hz, 1H), 5.54 (d, J=1.5 Hz, 1H), 4.17-4.11 (m, 1H), 3.99 (dt, J=12.0,3.0 Hz, 2H), 3.58-3.54 (m, 2H), 2.37-2.30 (m, 3H), 2.17-2.08 (m, 2H),2.03-1.94 (m, 1H), 1.71-1.58 (m, 1H), 0.59 (d, J=13.0 Hz, 1H); ¹³C NMR(125 MHz, C₆D₆) δ: 128.8, 106.5, 96.6, 77.6, 70.6, 62.8, 60.8, 53.2,39.1, 31.4, 25.1 HRMS (ESI) m/z: [M+H]+ calcd for C₂₄H₃₁Cl₂I₂O₄,706.9683. found, 706.9658.

To a solution of TES-protected alcohol YS-14 (16.2 g, 16.7 mmol) inCH₂Cl₂ (167 mL) was added co-solvent mixture TFA/H₂O/CH₂Cl₂ (4:1:10)(25.6 mL) at 0° C. The reaction mixture was stirred vigorously at roomtemperature until TLC showed a complete disappearance of the startingmaterial (around 0.5 h). The reaction was diluted with EtOAc, quenchedcarefully with sat. NaHCO₃ aq., and the organic phases were separatedand the aqueous phase was extracted with EtOAc three times, washed withbrine. The combined organic phases were dried over Na₂SO₄ andconcentrated. The crude material was flushed through a short silica gelcolumn to afford the ynone Y-27b (10.9 g, 79%) as colorless oil.

Coupling Product Y-27b:

¹H NMR (500 MHz, C₆D₆) δ: 6.14 (d, J=9.3 Hz, 1H), 5.63 (s, 1H), 5.50 (s,1H), 4.11 (s, 1H), 4.07 (s, 1H), 4.07 (t, J=7.4 Hz, 2H), 3.87-3.81 (m,2H), 3.70 (td, J=10.0, 4.0 Hz, 2H), 3.33 (s, 3H), 2.79 (dd, J=9.5, 2.1Hz, 1H), 2.47 (ddd, J=17.9, 9.2, 5.2 Hz, 1H), 2.39-2.27 (m, 2H), 2.18(m, 2H), 2.06-1.99 (m, 2H), 1.75-1.69 (m, 1H), 1.61-1.54 (m, 1H),1.35-1.20 (m, 2H), 1.03 (s, 9H), 0.80 (s, 9H), 0.16 (m, 6H), −0.10 (s,3H), −0.11 (s, 3H); ¹³C NMR (125 MHz, C₆D₆) δ: 170.5, 128.5, 128.0,105.8, 91.2, 84.2, 79.2, 75.4, 74.3, 72.8, 72.7, 65.0, 63.8, 59.8, 52.8,50.8, 42.0, 40.3, 30.8, 30.1, 29.3, 25.9, 25.7, 18.4, 18.0, −4.1, −5.0,−5.7. HRMS (ESI) m/z: [M+Na]⁺ calcd for C₃₃H₅₆ClIO₈Si₂Na, 821.2145.found, 821.2147.

Synthesis Outlined in FIG. 25

To a 0° C. solution of acetylenic ketone Y-27b (74.5 mg, 93 μmol) inMeCN (1.9 mL, 0.05 M) and imidazole (443 mg, 6.5 mmol) in a plastic vialwas added HF-pyridine complex (70% HF content, 0.17 mL, 6.5 mmol) andstirred at room temperature for 70 h. Then triethylamine (856 mg, 8.5mmol) was added into the reaction mixture at 0° C. After stirring atroom temperature for 1 h, the reaction was carefully neutralized withsaturated NaHCO₃ solution and NaHCO₃ solid. The mixture was extractedwith EtOAc four times, the combined organic phase was washed by 1 N HClsolution and brine before drying over anhydrous Na₂SO₄, and thenconcentrated under reduced pressure. The crude material was purified byflash column chromatography on silica gel to afford double oxy-Michaelproduct Y-29 (46.3 g, 81%).

Double Oxy-Michael Product Y-29:

[α]²⁰ _(D) −15.9 (c 1.20, CHCl₃); ¹H NMR (500 MHz, C₆D₆) δ: 5.71 (d,J=1.5 Hz, 1H), 5.57 (d, J=1.5 Hz, 1H), 4.62-4.57 (dt, J=10.5, 4.5 Hz,1H), 4.19 (s, 1H), 3.94 (m, 1H), 3.90 (m, 1H), 3.84 (m, 1H), 3.80-3.77(m, 2H), 3.48 (s, 1H), 3.31 (s, 3H), 2.82 (d, J=15.0 Hz, 1H), 2.74 (d,J=9.6 Hz, 1H), 2.52 (d, J=15.0 Hz, 1H), 2.45 (m, 1H), 2.29 (m, 1H), 2.25(m, 2H), 2.15-2.10 (m, 1H), 2.04-1.99 (m, 2H), 1.60-1.53 (m, 2H);1.29-1.26 (m, 2H), 1.11-1.08 (m, 1H); ¹³C NMR (125 MHz, C₆D₆) δ: 206.7,171.5, 129.3, 108.0, 106.7, 78.5, 78.3, 77.8, 76.1, 75.5, 68.7, 67.5,61.0, 53.8, 51.5, 45.6, 41.6, 40.9, 31.4, 31.0, 29.9. HRMS (ESI) m/z:[M+Na]⁺ calcd for C₂₁H₂₈ClIO₈Na, 593.0410; found, 593.0407.

To a solution of double oxy-Michael product Y-29 (473 mg, 0.83 mmol) ina mixture of anhydrous THF (69 mL, 0.012M) and allyl alcohol (6.9 mL)was added Hf(OTf)₄ (161 mg, 0.21 mmol). The reaction was stirred for 3 hat room temperature in a glovebox. Then the reaction was quenched bytriethylamine, diluted with EtOAc, and quenched with saturated NaHCO₃solution. The aqueous layer was extracted with EtOAc, and the combinedorganic phase was washed with brine, dried over Na₂SO₄ then concentratedunder vacuum. Purification of the residual material by flashchromatograph on silica gel afforded halichondrin-C C1-C19 buildingblock Y-10 (374 mg, 74%) as white foam.

Halichondrin-Y-C C1-C19 Building Block Y-10:

[α]²⁰ _(D) −37.0 (c 1.0, CHCl₃); ¹H NMR (500 MHz, C₆D₆) δ: 5.71 (d,J=1.5 Hz, 1H), 5.57 (d, J=1.5 Hz, 1H), 4.62-4.57 (dt, J=10.5, 4.5 Hz,1H), 4.19 (s, 1H), 3.94 (m, 1H), 3.90 (m, 1H), 3.84 (m, 1H), 3.80-3.77(m, 2H), 3.48 (s, 1H), 3.31 (s, 3H), 2.82 (d, J=15.0 Hz, 1H), 2.74 (d,J=9.6 Hz, 1H), 2.52 (d, J=15.0 Hz, 1H), 2.45 (m, 1H), 2.29 (m, 1H), 2.25(m, 2H), 2.15-2.10 (m, 1H), 2.04-1.99 (m, 2H), 1.60-1.53 (m, 2H);1.29-1.26 (m, 2H), 1.11-1.08 (m, 1H); ¹³C NMR (125 MHz, C₆D₆) δ: 206.7,171.5, 129.3, 108.0, 106.7, 78.5, 78.3, 77.8, 76.1, 75.5, 68.7, 67.5,61.0, 53.8, 51.5, 45.6, 41.6, 40.9, 31.4, 31.0, 29.9. HRMS (ESI) m/z:[M+H]⁺ calcd for C₂₄H₃₃ClIO₈, 611.0942. found, 611.0959.

Synthesis Outlined in FIG. 26

Synthesis of Halichondrin-B C1-C19 Building Block Y-9 from E-Isomer(E)-Y-31

To a 0° C. solution of acetylenic ketone Y-27b (331 mg, 0.36 mmol) inpyridine (3.0 mL, 36.0 mmol) and MeCN (8.1 mL) in a plastic vial wasadded HF-pyridine complex (70% HF content, 0.95 mL, 36.2 mmol) andstirred at room temperature. Once the reaction was completed, thereaction was cooled to 0° C. and carefully neutralized with saturatedNaHCO₃ solution and NaHCO₃ solid. The mixture was extracted with EtOAcfour times, and the combined EtOAc extracts were dried over anhydrousNa₂SO₄ and concentrated under reduced pressure. The crude material waspurified by flash column chromatography on silica gel to afford (E)-Y-31(161 mg, 65%) and (Z)-Y-31 (18.4 mg, 7%).

Enone (E)-Y-31:

[α]²⁰ _(D) −125.3 (c 0.12, CHCl₃); ¹H NMR (600 MHz, C₆D₆) δ: 5.75 (1H,d, J=0.8 Hz, H-13), 5.73 (ddd, J=1.5, 1.2, 0.9 Hz, 1H), 5.57 (d, J=1.5Hz, 1H), 5.10 (ddd, J=7.9, 7.3, 0.8 Hz, 1H), 4.86 (d, J=7.3 Hz, 1H),4.30 (ddd, J=10.5, 9.8, 4.8 Hz, 1H), 4.08 (dddd, J=9.8, 7.6, 5.9, 3.2Hz, 1H), 3.91 (dd, J=4.7, 1.6 Hz, 1H), 3.85 (1H, dd, J=8.5, 7.9 Hz, 1H),3.78 (dd, J=8.5, 4.7 Hz, 1H), 3.68 (dddd, J=10.9, 8.8, 4.3, 1.9 Hz, 1H),3.39 (s, 3H), 2.54 (dd, J=9.8, 1.6 Hz, 1H), 2.53 (ddd, J=17.1, 8.5, 5.3Hz, 1H), 2.42-2.34 (m, 3H), 2.33 (dd, J=15.5, 8.8 Hz, 1H), 2.04-1.96 (m,3H), 1.73 (dddd, J=14.6, 9.8, 8.5, 5.3 Hz, 1H), 1.27-1.15 (m, 2H), 1.02(s, 9H), 0.98-0.91 (m, 1H), 0.19 (s, 3H), 0.16 (s, 3H); ¹³C NMR (150MHz, C₆D₆) δ: 198.0, 176.5, 170.9, 128.8, 106.3, 102.3, 77.4, 77.1,74.7, 71.1, 69.7, 67.7, 66.0, 60.9, 53.6, 51.1, 40.5, 40.2, 31.9, 30.1,29.9, 26.0 (3C), 18.7, −4.4, −4.6. HRMS (ESI) m/z: [M+H]⁺ calcd forC₂₇H₄₃ClIO₈Si, 685.1455. found, 685.1455.

To a slurry of tetramethylammonium triacetoxyborohydride (71 mg, 0.27mmol) in CH₃CN (90 μL) at −30° C. was added acetic acid (90 μL) and themixture was stirred at this temperature for 30 min. The mixture was thenadded to a solution of (E)-Y-31 (23.1 mg, 33.7 μmol) in CH₃CN (20 μL).The resulting solution was stirred at −30° C. and slowly warmed up to 0°C. The reaction was quenched by addition of an aqueous solution ofsodium, potassium tartrate followed by solid Na₂CO₃. The aqueous phasewas extracted with CH₂Cl₂, and the combined organic phase was dried overNa₂SO₄ and concentrated under vacuum. Purification of residual materialby flash column chromatograph on silica gel afforded a ketone Y-32(colorless oil, 19.6 mg, 85% yield) as a ˜5:1 mixture of Y-12α and Y-12βdiastereomers.

To ketone Y-32 (17.5 mg, 25.4 μmol) was added TBAF solution in THF (2equiv, buffered with 0.25 equiv. of imidazole hydrochloride) at roomtemperature. After stirring for 0.5 h at the same temperature, thereaction solution was diluted with DCM followed by EtOAc. The mixturewas filtered through silica gel pad (5% MeOH in EtOAc) to remove TBAFresidue. After removal of the solvent, the crude diol Y-33 (13.2 mg, 91%yield, ˜1:1 mixture of Y-12α and Y-12β diastereomers) was directly usedfor the next step.

The crude Y-33 was dissolved in CH₂Cl₂ (0.5 mL) and treated with PPTS (2equiv) at room temperature. After stirring for 2 h at room temperature,the solvent was removed, to give the residue that was purified by PTLC,to furnish halichondrin-B C1-C19 building block Y-9 (6.1 mg, 46%) andundesired Y-12a Y-33 (6.0 mg, 45%).

Halichondrin-B C1-C19 Building Block 9:

yellow oil, [α]_(D) ²⁰=−25.8 (c 1.0, CHCl₃); ¹H NMR (500 MHz, C₆D₆) δ:5.83 (s, 1H), 5.67 (s, 1H), 4.41 (dt, J=10.0 Hz, 4.0 Hz, 1H), 4.02 (dt,J=10.0 Hz, 5.0 Hz, 1H), 4.36 (s, 1H), 4.14 (sep, J=5.0 Hz, 2H), 4.08 (t,J=5.0 Hz, 1H), 3.89 (dd, J=6.5 Hz, 5.0 Hz, 1H), 3.76-3.69 (m, 1H), 3.66(dd, J=6.5 Hz, 4.0 Hz, 1H), 3.30 (s, 3H), 2.58 (dt, J=15.0 Hz, 5.0 Hz,2H), 2.51 (dd, J=15.5 Hz, 3.0 Hz, 1H), 2.17 (dd, J=16.0 Hz, 5.0 Hz, 1H),2.22-2.12 (m, 1H), 2.10-1.75 (m, 5H), 1.44-1.37 (m, 1H), 1.35 (dd,J=13.0 Hz, 5.0 Hz, 1H), 1.33-1.16 (m, 2H); ¹³C NMR (125 MHz, C₆D₆) δ:170.9, 128.8, 109.7, 106.8, 82.4, 80.8, 78.5, 76.9, 74.9, 74.7, 74.2,68.5, 61.8, 53.4, 51.1, 47.4, 40.7, 36.3, 32.4, 30.8, 30.7; HRMS (ESI)m/z: [M+H]⁺ calcd for C₂₁H₂₉ClIO₇, 555.0646; found, 555.0655.

On comparison of spectroscopic and chromatographic properties,halichondrin-B C1-C19 building block Y-9 and diol Y-33 thus obtainedwere found to be identical with the authentic samples synthesized via adifferent route (Yan, W.; Li, Z.; Kishi, Y. J. Am. Chem. Soc. 2015, 137,0000). Also, that previous work has demonstrated that diol Y-33 with theundesired C12α-stereochemistry can be transformed to Y-9 viaion-exchange resin based device or base-induced equilibration, followedby PPTS treatment.

Reduction of (Z)-Y-31 to Y-32

Following the procedure given above for reduction of (E)-Y-31, (Z)-Y-31(2.7 mg) was transformed into ketone product that was identical to Y-32,based on comparison of spectroscopic and chromatographic properties.

Synthesis of Halichondrin-B C1-C19 Building Block Y-9 from a (E)- and(Z)-Mixture of Y-31

Following the procedures given above, Y-27b (51 mg) was transformed intohalichondrin-B C1-C19 building block Y-9 (12.3 mg), withoutisolation/separation of intermediates.

In this experiment, the crude Y-33 (13.2 mg, a 1:1 Y-12α- andY-12β-diastereomeric mixture) was dissolved in 2 mL EtOH in a black-capvial and then connected to ion-exchange resin based device ((a) Namba,K.; Jun, H. S.; Kishi, Y. J. Am. Chem. Soc. 2004, 126, 7770. (b)Kaburagi, Y.; Kishi, Y. Org. Lett. 2007, 9, 723). The reaction completedin 10 h, and both basic and acidic resins were washed with ethanol (3mL). The combined EtOH solutions were concentrated under reducedpressure. The residue was passed through a short silica gel plug(elution with hexanes/EtOAc=10:1 to 1:1) to give product Y-9 (12.3 mg,34% overall yield from Y-27b).

Synthetic Plan

All of C1-C19 building blocks Y-8-Y-10 could be synthesized fromacetylenic ketone Y-15a,b, by adjusting its oxidation state (FIG. 20).C1-C19 building block Y-8 of halichondrin A was synthesized with thisstrategy (Halichondrin As: Ueda, A.; Yamamoto, A.; Kato, D.; Kishi, Y.J. Am. Chem. Soc. 2014, 136, 5171). In the halichondrin A synthesis,acetylenic ketone Y-15a was synthesized via two (Ni)/Cr-mediatedcouplings. In light of the successful selective activation/coupling ofpoly-halogenated nucleophile Y-17 in a Ni/Cr-mediated coupling, it wasrecognized that Y-15a,b could be synthesized in one step, cf.,Y-11+Y-16a,b→Y-15a,b. In the halichondrin B series, a selectiveactivation/coupling of the trans-β-bromoenone was realized with use of atrace amount of a polyether-type Ni-catalyst (Uemura, D.; Takahashi, K.;Yamamoto, T.; Katayama, C.; Tanaka, J.; Okumura, Y.; Hirata, Y. J. Am.Chem. Soc. 1985, 107, 4796; Hirata, Y.; Uemura, D. Pure Appl. Chem.1986, 58, 701). Activation of halo-acetylenes is achieved with a traceamount of Ni-catalyst or even no added Ni-catalyst. A selectiveactivation of the halo-acetylene over the vinyl iodide or bromide andsaturated chloride is established in Y-16a,b (Pettit, G. R.; Herald, C.L.; Boyd, M. R.; Leet, J. E.; Dufresne, C.; Doubek, D. L.; Schmidt, J.M.; Cerny, R. L.; Hooper, J. N. A.; Ritzler, K. C. J. Med. Chem. 1991,34, 3339; Pettit, G. R.; Tan, R.; Gao, F.; Williams, M. D.; Doubek, D.L.; Boyd, M. R.; Schmidt, J. M.; Chapuis, J.-C.; Hamel, E.; Bai, R.;Hooper, J. N. A.; Tackett, L. P. J. Org. Chem. 1993, 58, 2538; Litaudon,M.; Hart, J. B.; Blunt, J. W.; Lake, R. J.; Munro, M. H. G. TetrahedronLett. 1994, 35, 9435; Litaudon, M.; Hickford, S. J. H.; Lill, R. E.;Lake, R. J.; Blunt, J. W.; Munro, M. H. G. J. Org. Chem. 1997, 62, 1868;Hickford, S. J. H.; Blunt, J. W.; Munro, M. H. G. Bioorg. Med. Chem.2009, 17, 2199).

Model Study on Coupling Efficiency

Six halo-acetylenes Y-18a-c and Y-19a-c and aldehyde Y-20 were chosen(FIG. 21). The coupling efficiency of halo-acetylenic ketones Y-18a-cover halo-acetylenic ketals Y-19a-c, under the coupling conditions: 10mol % Cr-catalyst, prepared from (S)-sulfonamide Y-21, Ni-catalyst Y-22(0.05 mol %) or no added Ni-catalyst, Zr(cp)₂Cl₂ (1.5 eq), Mn (2 eq),and LiCl (2 eq) in MeCN ([C] 0.4M) at room temperature were compared(Hart, J. B.; Lill, R. E.; Hickford, S. J. H.; Blunt, J. W.; Munro, M.H. G. Drugs from the Sea, Ed. Fusetani, N., Ed.; Karger, Basel, 2000,134; Jackson, K. L.; Henderson, J. A.; Phillips, A. J. Chem. Rev. 2009,109, 3044). This experiment demonstrated: (1) halo-acetylenic ketonesY-18a-c gave the desired product in only modest yields, with the orderof coupling efficiency being Y-18b (49%)>Y-18c (20%)>Y-18a (11%); (2)halo-acetylenic ketals Y-19a,b gave the desired product in good yields,with the order of coupling efficiency being Y-19b (93%)>Y-19a(82%)>>Y-19c (8%); (3) no significant difference was detected between0.05 mol % and no added Ni-catalyst. In addition, a brief study onsolvents and concentration revealed: (1) the solvent choice beingEtCN>MeCN>DME>THF, but not DMF and (2) the optimum concentration being arange of 0.4-0.8 M.

Coupling in the Halichondrin Series

The nucleophiles Y-24a,b were readily prepared from the previouslyreported, optically pure aldehydes Y-23a,b (FIG. 22) (Hart, J. B.; Lill,R. E.; Hickford, S. J. H.; Blunt, J. W.; Munro, M. H. G. Drugs from theSea, Ed. Fusetani, N., Ed.; Karger, Basel, 2000, 134; Jackson, K. L.;Henderson, J. A.; Phillips, A. J. Chem. Rev. 2009, 109, 3044). Withrespect to the electrophile, several possible C8,C9-protecting groupswere screened, thereby showing bis-TBS aldehyde Y-27 as the best option((Pettit, G. R.; Herald, C. L.; Boyd, M. R.; Leet, J. E.; Dufresne, C.;Doubek, D. L.; Schmidt, J. M.; Cerny, R. L.; Hooper, J. N. A.; Ritzler,K. C. J. Med. Chem. 1991, 34, 3339; Pettit, G. R.; Tan, R.; Gao, F.;Williams, M. D.; Doubek, D. L.; Boyd, M. R.; Schmidt, J. M.; Chapuis,J.-C.; Hamel, E.; Bai, R.; Hooper, J. N. A.; Tackett, L. P. J. Org.Chem. 1993, 58, 2538; Litaudon, M.; Hart, J. B.; Blunt, J. W.; Lake, R.J.; Munro, M. H. G. Tetrahedron Lett. 1994, 35, 9435; Litaudon, M.;Hickford, S. J. H.; Lill, R. E.; Lake, R. J.; Blunt, J. W.; Munro, M. H.G. J. Org. Chem. 1997, 62, 1868; Hickford, S. J. H.; Blunt, J. W.;Munro, M. H. G. Bioorg. Med. Chem. 2009, 17, 2199).

Compounds Y-11 and Y-24a were subjected to the coupling reaction underthe condition used in the model study, to furnish the desired productY-27a in 55% yield, with a 10:1 stereoselectivity. The structure ofY-27a was established via correlation with the authentic sample obtainedin the previous route.^(5c) As anticipated, a product derived throughactivation of the vinyl iodide or saturated chloride present in Y-24awas not detected.

In order to improve the observed stereoselectivity, the toolbox approachwas used and a representative set of sulfonamides was screened (FIG. 23)(Guo, H.; Dong, C.-G.; Kim, D.-S.; Urabe, D.; Wang, J.; Kim, J. T.;Xiang Liu, Sasaki, T.; Kishi, Y. J. Am. Chem. Soc. 2009, 131, 15387).This screening showed that: (1) as previously observed, thestereochemistry outcome was dictated by the substrate structure ratherthan the chirality present in the Cr-catalyst and (2) for this coupling,sulfonamides in the (R)-series gave a better stereoselectivity than thecorresponding sulfonamides in the (S)-series. Among the tested ligands,sulfonamide (R)-21 and Ni-catalyst 22 were chosen for the followingstudy.

It was found that the coupling rate with TES-Cl was slower than thatwith Zr(cp)₂Cl₂, yet the coupling yield with TES-Cl was noticeablybetter than that with Zr(cp)₂Cl₂, i.e., 85% with TES-Cl vs. 70% withZr(cp)₂Cl₂. Although its mechanistic reason was not clear, the TES-Ccondition made it possible to achieve the proposed coupling with thesynthetically useful efficiency.

As noted before, Cr-mediated coupling of a halo-acetylene with analdehyde is known to proceed with only a trace amount of Ni-catalyst oreven no added Ni-catalyst (Aicher, T. D.; Kishi, Y. Tetrahedron Lett.1987, 28, 3463. (b) Usanov, D.; Yamamoto, H. J. Am. Chem. Soc. 2011,133, 1286). The coupling of Y-11+Y-24a→Y-27a was studied “with” and“without” added Ni-catalyst, thereby showing the coupling efficiency tobe comparable. There is no definite experimental evidence to concludewhether this coupling involves activation of bromoacetylene withNi-catalyst, followed by Cr-mediated coupling, or activation/couplingwith only a Cr-catalyst. The homo-dimer of bromoacetylene was isolatedin ca. 0.3% yield (based on Y-24a) in the coupling without addedNi-catalyst. Therefore, the coupling is referred to as (Ni)/Cr-mediatedreaction.

The coupling studies were carried out with both Y-24a,b simultaneouslyand obtained the virtually identical results in the both series,although a small reduction in yield was noticed in the Y-24b-series.

Synthesis of C1-C19 Building Blocks of Halichondrins A-C from the CommonSynthetic Intermediate Y-27

Synthesis of C1-C19 Building Block of Halichondrin A

In the halichondrin A synthesis, the transformation of Y-27a into C1-C19building block Y-8 was established (FIG. 25). The key reactions in thistransformation included: (1) a selective TBS-deprotection to formE-enone Y-28 and (2) a highly stereoselective DMDO-oxidation tointroduce the C13 hydroxyl group. The C1-C19 building block Y-8 bearsthe C19 vinyl bromide, because the corresponding vinyl iodide was notcompatible with the DMDO oxidation (Halichondrin As: Ueda, A.; Yamamoto,A.; Kato, D.; Kishi, Y. J. Am. Chem. Soc. 2014, 136, 5171).

Synthesis of C1-C19 Building Block of Halichondrin C

In the halichondrin Y-C synthesis, a synthetic route to construct thepolyclic ring system from an acetylenic ketone was reported(Halichondrin Cs: Yamamoto, A.; Ueda, A.; Bremond, P.; Tiseni, P. S.;Kishi, Y. J. Am. Chem. Soc. 2012, 134, 893). There was no unexpecteddifficulty in the transformation of Y-27b to Y-10 in 60% overall yield(FIG. 25). The key reactions in this transformation included: (1) doubleoxy-Michael addition of C8,C9-hydroxyl groups to the acetylenic ketoneto form ketal Y-29 and (2) Hf(OTf)₄-induced conversion of the doubleoxy-Michael product Y-29 to polycycle Y-10 in ally alcohol. Thestructure Y-10 was fully supported by the spectroscopic data (HR-MS, ¹Hand ¹³C NMR).

Synthesis of C1-C19 Building Block of Halichondrin B

In order to synthesize C1-C19 building block Y-9 in the halichondrin Bseries from the common synthetic intermediate, an acetylene-to-olefinreduction was needed and tested first the reactivity of Y-27b and itsC11-OTBS derivative against CuH, HN═NH, and CrCl₂ (FIG. 26), therebyindicating that the C11-OTBS substrate exhibited a very poor reactivity.Based on this observation, Y-27b was used for a search of a satisfactoryreducing reagent/condition. Among reagents tested, (BDP)CuH, a StrykerCuH modified by Lipshutz, gave a mixture of E- and Z-enones (FIG. 26).As discussed in the preceding paper, Z-enone was found to form readilythe furan (Yan, W.; Li, Z.; Kishi, Y. J. Am. Chem. Soc. 2015, 137,0000). Thus, although it was a minor product, Z-enone was wasted. Thisreduction gave the desired E-enone Y-31 as the major product, but theisolated yield varied from 55% up to 80%.

Under this circumstance, (Me)₄NBH(OAc)₃ reduced the vinylogous esterE-Y-31 to give Y-32 in 80% yield as a 5:1 mixture of Y-12α:Y-12βdiastereomers. (Me)₄NBH(OAc)₃ is so-called hydroxyl-directing setting.It was also found that the substrate with the C11-OH masked with a TBSwas inert to the reduction.

It was observed that (Me)₄NBH(OAc)₃ reduction of the correspondingZ-enone Z-Y-31 gave Y-32 as a mixture of 1 Y-2α:Y-12β stereoisomers.Thus, for the preparative purpose, it was not necessary to separate E-and Z-enones Y-31.

On TBAF treatment, Y-32 furnished Y-33 as a ˜1:1 mixture of Y-12α:Y-12βdiastereomers. With ion-exchange resin based device, this mixture wastransformed cleanly to C1-C19 building block Y-9 of halichondrin Bwithout isolation/separation/equilibration of intermediates. Oncomparison of spectroscopic data (¹H and ¹³C NMR, MS, TLC), Y-9 thusobtained was found to be superimposable on the authentic sample (Yan,W.; Li, Z.; Kishi, Y. J. Am. Chem. Soc. 2015, 137, 0000).

A unified synthesis of the C1-C19 building blocks Y-8-Y-10 ofhalichondrins A-C was developed from the common synthetic intermediatesY-27a,b. Acetylenic ketones Y-27a,b were in turn synthesized viaselective activation/coupling of poly-halogenated nucleophiles Y-24a,bwith aldehyde Y-11 in a (Ni)/Cr-mediated coupling reaction. Comparedwith Ni/Cr-mediated couplings of vinyl iodides and aldehydes, this(Ni)/Cr-mediated coupling exhibited two unique features. First, thecoupling was found to proceed with a trace amount or no addedNi-catalyst. Second, TES-Cl, a dissociating agent to regenerate theCr-catalyst, was found to give a better yield than Zr(cp)₂Cl₂. Anadjustment of the oxidation state was required to transform acetylenicketones Y-27a,b into C1-C19 building blocks Y-8 and Y-9 of halichondrinsA and B, respectively. In the halichondrin B series, a hydroxyl-directed(Me)₄NBH(OAc)₃ reduction of E- and Z-vinylogous esters Y-31 was foundcleanly to achieve the required transformation, whereas a DMDO oxidationof E-vinylogous ester Y-28 allowed to introduce the C13 hydroxyl groupwith a high stereoselectivity in the halichondrin A series. In thehalichondrin C series, Hf(OTf)₄ was used to convert double oxy-Michaclproduct Y-29 into C1-C19 building block Y-10.

Synthesis of C20-C38 Building Blocks

One of the key intermediates in the halichondrin syntheses describedherein is the C20-C38 aldehyde B, which can be synthesized from methylester A. As described herein, this transformation can be achieved in 6or 7 synthetic steps as depicted in Scheme 4.

Following the previously reported method (J. Am. Chem. Soc. 136, 5171(2014)), both 5 and 6 can be converted into the right half ofhalichondrins A-C in 4 steps (1. Ni/Cr-mediated coupling, 2.base-induced cyclization, 3. ester/acetate hydrolysis, 4.macrolactonization), with modification of the second step of sequence,i.e., CaCO₃ or SrCO₃ in aq. i-BuOH at 100° C., instead of AgOTf-Ag₂O inTHF at 0° C.

Experimental Procedures for the Synthesis of C20-C38 Building Blocks

To a solution of P-1 (132 mg) in CH₂Cl₂ (2.8 mL) at −78° C. was addedDIBAL (1.0 M in hexane, 0.43 mL). After stirred for 1 h at the sametemperature, the reaction was quenched with EtOAc (5 mL) at −78° C. and10% aqueous Rochelle's salt (5 mL), then stirred for 1 h. The mixturewas extracted with EtOAc, and the organic layer was dried over Na₂SO₄,filtered, and concentrated. Flash silica gel column chromatography ofthe residue (EtOAc/hexanes 10% to 60%) gave P-2 (108 mg, 89% yield).¹H-NMR (600 MHz, C₆D₆) δ: 10.05 (1H, dd, J=2.9, 2.9 Hz), 7.19 (2H, m),6.78 (2H, m), 5.13 (1H, ddd, J=9.1, 9.1, 4.7 Hz), 4.42 (1H, J=11.2 Hz),4.24 (1H, J=11.2 Hz), 3.97 (1H, dd, J=11.4 Hz), 3.55 (1H, dd, J=3.5, 3.5Hz), 3.51 (1H, ddd, J=5.0, 2.8, 2.8 Hz), 3.30 (1H, dd, J=3.3, 3.3 Hz),3.28 (3H, s), 3.13 (1H, dd, 2.9, 2.9 Hz), 2.96 (1H, dd, J=9.4, 2.9 Hz),2.92 (1H, m), 2.76 (1H, ddd, J=15.3, 4.7, 2.9 Hz), 2.46 (1H, ddd,J=15.3, 8.2, 2.9 Hz), 2.26 (1H, m), 1.95 (1H, ddd, 14.7, 2.6, 2.6 Hz),1.69 (1H, m), 1.56 (1H, m), 1.21-1.30 (7H, m), 0.87 (3H, dd, J=7.6, 7.6Hz).

To a mixture of CrCl₂ (3.6 mg), sulfonamide-I (15.9 mg), and protonsponge (6.8 mg) in a glove box was added MeCN (0.73 mL) and stirred for2 h at room temperature. In a separate flask, P-2 (126 mg), P-3 (170mg), LiCl (24.6 mg), Mn (63.7 mg), Cp₂ZrCl₂ (84.8 mg) were mixedtogether and the above Cr-complex solution was transferred to the flask.Then (Me)₆Phen-NiCl₂ (5.7 mg) was added. After 1 hr, additional(Me)₆Phen-NiCl₂ (5.7 mg) was added. The reaction mixture was stirred for3 h (total) at room temperature, and diluted with EtOAc. Florisil wasadded and the suspension was vigorously stirred for 30 min. Theresultant suspension was filtered through a short pad of silica gel (1cm) with EtOAc, and concentrated. The crude material was purified withsilica gel flash column chromatography (EtOAc/hexanes 0% to 50%) to giveP-4 (170 mg, 83% yield). ¹H-NMR (600 MHz, C₆D₆) δ: 7.25 (2H, m), 6.85(2H, m), 5.67 (1H, s), 5.09 (1H, s), 4.83 (1H, m), 4.74 (1H, d, J=10.6Hz), 4.51 (1H, d, J=11.2 Hz), 4.44 (1H, s), 4.36 (1H, d, J=11.2 Hz),4.07 (1H, dd, J=11.4, 11.4 Hz), 3.57 (1H, m), 3.48 (1H, m), 3.40-3.34(5H, m), 3.33 (3H, s), 3.27 (2H, m), 3.05 (1H, m), 2.97-2.90 (2H, m),2.74 (1H, m), 2.61 (2H, m), 2.49 (1H, brd, J=14.1 Hz), 2.38 (1H, m),2.27-2.19 (2H, m), 2.13 (1H, dd, J=14.7, 4.7 Hz), 1.92 (1H, dd, J=14.7,7.0 Hz), 1.85 (1H, ddd, J=14.8, 2.6, 2.6 Hz), 1.79 (1H, ddd, J=13.9,10.3, 10.3 Hz), 1.69 (1H, m), 1.64-1.55 (4H, m), 1.42 (3H, d, J=7.0 Hz),1.34 (3H, s), 1.18 (1H, ddd, J=14.8, 4.3, 4.3 Hz), 0.88 (3H, d, J=7.6Hz), 0.75 (3H, s), 0.68 (3H, s).

To a solution of P-4 (100 mg) in CH₂Cl₂ (2.8 mL) was addedtriethylsilane (0.68 mL). The mixture was cooled to −78° C. then TESOTf(0.39 mL) was added. After being stirred for 90 min at the sametemperature the reaction was quenched with CH₂Cl₂ (3 mL) wetted withsaturated aqueous NaHCO₃, then saturated aqueous NaHCO₃ (3 mL). Themixture was warmed to room temperature, and then extracted with EtOAc.The organic layer was washed with saturated aqueous NaCl, dried overNa₂SO₄, filtered, and concentrated. Silica gel flash columnchromatography of the residue (EtOAc/hexanes 50% to 100% then MeOH/EtOAc0.5%) gave a (55 mg, 88%). ¹H-NMR (600 MHz, CD₃OD) δ: 4.93 (1H, brs),4.83 (1H, brd, J=1.8 Hz), 3.96 (1H, dd, J=6.0 Hz), 3.92 (1H, m), 3.89(1H, dd, J=6.5, 6.5 Hz), 3.73-3.66 (2H, m), 3.65 (3H, s), 3.61 (1H, m),3.54 (1H, dd, J=8.8, 4.7 Hz), 3.51 (1H, m), 3.41-3.37 (2H, m), 2.53-2.39(2H, m), 2.30 (1H, m), 2.20 (1H, ddd, J=14.2, 5.5, 5.5 Hz), 2.15 (1H,ddd, J=14.7, 2.9, 2.9 Hz), 1.96-1.85 (4H, m), 1.84-1.64 (5H, m), 1.16(3H, d, J=7.0 Hz), 1.10 (3H, d, J=6.5 Hz), 1.03 (1H, dd, J=24.0, 12.6Hz).

To a (5.0 mg) was added a solution of 2,2-dimethoxypropane (11 μL),2-methoxypropene (20 μL), PPTS (0.22 mg) in acetone (0.44 mL) at roomtemperature and the reaction was stirred for 1 day at room temperature.The reaction was quenched with saturated aqueous NaHCO₃. The mixture wasextracted with EtOAc, and the organic layer was washed with saturatedaqueous NaCl, dried over Na₂SO₄, filtered, and concentrated. Silica gelpreparative TLC purification (EtOAc) gave b (4.6 mg, 85% yield). ¹H-NMR(600 MHz, C₆D₆) δ: 4.95 (1H, brs), 4.74 (1H, brd, J=1.8 Hz), 4.51 (1H,m), 4.09 (1H, dd, J=8.2, 4.1 Hz), 3.99 (1H, m), 3.7 (1H, m), 3.65 (1H,m), 3.48 (1H, m), 3.43-3.34 (5H, m), 3.31 (1H, d, J=7.6 Hz), 3.15 (1H,dd, J=2.9, 2.9 Hz), 3.05 (1H, m), 2.46-2.40 (2H, m), 2.33 (1H, m), 2.26(1H, m), 2.19 (1H, ddd, J=14.4, 4.2, 4.2 Hz), 2.10 (1H, ddd, J=14.2,3.7, 3.7 Hz), 1.90 (1H, m), 1.76 (1H, m), 1.73-1.56 (3H, m), 1.39 (1H,ddd, J=14.1, 4.1, 4.1 Hz), 1.36 (3H, s), 1.29 (3H, s), 1.27 (1H, ddd,J=12.6, 4.4, 1.8 Hz), 1.16 (3H, d, J=7.6 Hz), 0.90 (1H, dd, J=24.1, 12.3Hz), 0.87 (3H, d, J=6.5 Hz).

To a solution of b (4.6 mg) in CH₂Cl₂ (0.2 mL) at −78° C. was addedDIBAL (1.0 M solution in hexane, 26 μL). After being stirred for 50 min,the reaction was quenched with EtOAc (5 mL) and 10% aqueous Rochelle'ssalt (5 mL). The mixture was warmed to room temperature then stirred for1 h, then extracted with EtOAc. The organic layer was washed withsaturated aqueous NaCl, dried over Na₂SO₄, filtered, and concentrated togive aldehyde-alcohol, which was used for the next step without furtherpurification.

To a solution of crude aldehyde-alcohol in CH₂Cl₂ (0.18 mL) at roomtemperature was added pyridine (7.1 μL), acetic anhydride (4.2 μL), andDMAP (1.0 mg). After being stirred for 70 min at the same temperature,the reaction was quenched with saturated aqueous NaHCO₃. The mixture wasextracted with EtOAc, and the organic layer was washed with saturatedaqueous NaCl, dried over Na₂SO₄, filtered, and concentrated. Silica gelflash column chromatography (EtOAc/hexanes 50%) gave P-5 (3.0 mg, 64%yield for 2 steps). ¹H-NMR (600 MHz, C₆D₆) δ: 9.54 (1H, t, J=1.5 Hz),5.03 (1H, s), 4.95 (1H, dd, J=9.1, 5.6 Hz), 4.80 (1H, brd, J=2.0 Hz),4.67 (1H, m), 4.12 (1H, dd, J=6.5, 6.5 Hz), 4.02 (1H, ddd, J=12.0, 10.0,2.1 Hz), 3.63 (1H, ddd, J=4.4, 4.4, 1.8 Hz), 3.61 (1H, dd, J=8.8, 4.1Hz), 3.40 (1H, ddd, J=11.9, 4.3, 4.3 Hz), 3.3 (1H, m), 3.09 (1H, dd,J=3.8, 3.8 Hz), 3.04 (1H, m), 2.35-2.17 (5H, m), 1.20 (1H, ddd, J=14.1,4.1, 4.1), 1.96 (1H, m), 1.82 (1H, m), 1.68 (3H, s), 1.62-1.54 (3H, m),1.43 (1H, ddd, J=14.1, 4.7, 4.7 Hz), 1.36 (3H, s), 1.30 (3H, s), 1.27(1H, ddd, J=13.0, 4.5, 2.2 Hz), 1.24 (3H, d, J=7.0 Hz), 0.92 (3H, d,J=6.5 Hz), 0.91 (1H, dd, J=23.5, 12.3 Hz).

To a solution of methyl allylic alcohol P-4 (25 mg) in CH₂Cl₂ (0.7 mL)was added triethylsilane (0.22 mL). After the mixture was cooled to −78°C., TESOTf (47 μL) was added. After being stirred for 15 min, thereaction was quenched CH2Cl₂ (2 mL) wetted with saturated aqueous NaHCO₃(2 mL) then saturated aqueous NaHCO₃ (2 mL). The mixture was extractedwith EtOAc. The organic layer was dried over sodium sulfate, filtered,and concentrated. Silica gel preparative TLC purification (EtOAc) gavemethyl diol c (14.5 mg, 74% yield). ¹H-NMR (600 MHz, CD₃OD) δ: 7.29 (2H,m), 6.89 (2H, m), 4.87 (1H, brs), 4.81 (1H, brd, J=1.8 Hz), 4.59 (1H, d,J=11.2 Hz), 4.48 (1H, d, J=11.2 Hz), 4.09 (1H, m), 3.89 (1H, m),3.80-3.75 (4H, m), 3.74-3.68 (2H, m), 3.64 (3H, s), 3.58-3.51 (2H, m),3.48 (1H, m), 3.35 (1H, m), 3.39-3.28 (3H, m), 2.50-2.37 (2H, m),2.29-2.10 (4H, m), 1.98-1.83 (3H, m), 1.82-1.64 (4H, m), 1.16 (3H, d,J=7.6 Hz), 1.09 (3H, d, J=6.5 Hz), 1.02 (1H, dd, J=24.0, 12.6 Hz).

To a solution of diol c (12.3 mg) in CH₂Cl₂ (0.22 mL) at −78° C. wasadded TBSOTf (15 μL). The reaction mixture was stirred for 50 min, andthen quenched with saturated aqueous NaHCO₃. The mixture was extractedwith EtOAc, and the organic layer was washed with saturated aqueousNaCl, dried over Na₂SO₄, filtered, and concentrated. Silica gel flashcolumn chromatography of the residue (EtOAc/hexanes 0% to 20%) gave 4(16.4 mg, 95% yield). ¹H-NMR (600 MHz, C₆D₆) δ: 7.28 (2H, m), 6.81 (2H,m), 5.11 (1H, brs), 4.81 (1H, brd, J=1.2 Hz), 4.50 (2H, dd, J=18.0, 11.4Hz), 4.27-4.19 (2H, m), 3.97 (1H, ddd, J=9.7, 9.7, 4.1 Hz), 3.78 (1H,m), 3.70 (1H, m), 3.60 (1H, ddd, J=9.7, 2.5, 2.5 Hz), 3.53 (1H, m), 3.45(1H, m), 3.39 (3H, s), 3.32 (1H, dd, J=6.2, 3.8 Hz), 3.30 (3H, s), 3.17(1H, dd, J=8.8, 8.8 Hz), 2.49 (1H, m), 2.44-2.35 (2H, m), 2.32-2.20 (2H,m), 2.16-2.03 (3H, m), 1.84-1.72 (3H, m), 1.61 (1H, ddd, J=14.1, 4.7,0.47 Hz), 1.35 (1H, ddd, J=12.3, 4.7, 1.8 Hz), 1.25 (3H, d, J=7.0 Hz),1.04 (9H, s), 1.03-0.94 (10H, m), 0.92 (3H, d, J=6.5 Hz), 0.14 (3H, s),0.13 (3H, s), 0.11 (3H, s), 0.05 (3H, s).

To a solution of d (16.4 mg) in CH₂Cl₂ (0.2 mL) at −78° C. was addedDIBAL (1.0 M in hexane, 41 μL). After being stirred for 50 min at thesame temperature, the reaction was quenched with EtOAc (5 mL) followedby 10% aqueous Rochelle's salt (5 mL). The mixture was stirred for 1 h,and then extracted with EtOAc. The organic layer was washed withsaturated aqueous NaCl, dried over Na₂SO₄, filtered, and concentrated,to give aldehyde, which was used for the next step without furtherpurification. ¹H-NMR (600 MHz, C₆D₆) δ: 7.26 (2H, m), 6.81 (2H, m), 5.12(1H, brs), 4.81 (1H, brd, J=1.8 Hz), 4.48 (1H, d, J=11.4 Hz), 4.42 (1H,dd, J=11.4 Hz), 4.23-4.14 (2H, m), 3.95 (1H, ddd, J=9.7, 9.7, 4.7 Hz),3.78 (1H, m), 3.67 (1H, m), 3.59 (1H, ddd, J=9.5, 2.9, 2.9 Hz), 3.52(1H, m), 3.37-3.18 (5H, m), 3.07 (1H, dd, J=8.8, 8.8 Hz), 2.38 (1H, m),2.31-2.01 (7H, m), 1.76 (1H, m), 1.65-1.46 (3H, m), 1.42-1.26 (2H, m),1.23 (3H, d, J=7.0 Hz), 1.04 (9H, s), 1.00 (9H, s), 0.97-0.88 (4H, m),0.14 (3H, s), 0.13 (3H, s), 0.11 (3H, s), 0.05 (3H, s).

To a solution of the above aldehyde in CH₂Cl₂ (0.6 mL) and phosphatebuffer (1.0 M, pH=7.0, 0.2 mL) was added DDQ (7 mg). The reaction wasstirred for 30 min then added another DDQ (7 mg). After being stirredfor additional 30 min, the reaction was quenched with 10% aqueousNa₂S₂O₃ (3 mL). The mixture was extracted with EtOAc. The organic layerwas washed with saturated aqueous NaCl, dried over Na₂SO₄, filtered, andconcentrated, to give alcohol C30-alcohol, which was used for next stepwithout further purifications.

To a solution of C30-alcohol in pyridine (0.2 mL) was added aceticanhydride (20 μL) and DMAP (1 mg). After being stirred for 30 min, thereaction was quenched with saturated aqueous NH₄Cl. The mixture wasextracted with EtOAc and the organic layer was washed with saturatedaqueous NaCl, dried over Na2SO₄, filtered and concentrated. Silica gelflash column chromatography of the residue (EtOAc/hexanes 0% to 30%)gave Y-6 (5.3 mg, 38% yield for 3 steps). ¹H NMR (600 MHz, C₆D₆) δ: 9.56(1H, dd, J=1.5 Hz), 4.99 (1H, br s), 4.96 (1H, dd, J=8.3, 7.5 Hz), 4.82(1H, d, J=1.2 Hz), 4.38 (1H, ddd, J=8.3, 5.6, 5.6 Hz), 4.08 (1H, dd,J=6.2, 6.2 Hz), 3.90 (1H, ddd, J=9.9, 9.6, 4.5 Hz), 3.75 (1H, ddd,J=9.9, 5.5, 4.2 Hz), 3.59 (1H, ddd, J=4.5, 4.1, 3.7 Hz), 3.49-3.42 (2H,m), 3.41-3.34 (1H, m), 3.18 (1H, dd, J=4.8, 3.7 Hz), 2.33-2.24 (3H, m),2.21 (1H, ddd, J=7.2, 7.2, 5.0 Hz), 2.15 (1H, ddd, J=14.4, 6.4, 5.6 Hz),2.09-2.00 (3H, m), 1.76-1.71 (1H, m), 1.69 (3H, s), 1.62-1.56 (2H, m),1.48 (1H, ddd, J=14.4, 4.5, 4.5 Hz), 1.30 (1H, ddd, J=12.5, 4.2, 2.1Hz), 1.21 (3H, d, J=7.3 Hz), 1.02 (9H, s), 1.01 (9H, s), 0.93 (3H, d,J=6.4 Hz), 0.94-0.89 (1H, m), 0.11 (3H, s), 0.11 (6H, s), 0.04 (3H, s).

Using the following sequence, vinyl iodide P-3 was prepared from thepreviously reported e. To a solution of e (594 mg) in THF (4.9 mL) atroom temperature was added a mixture of TBAF (1.0 M in THF, 1.96 mL) andimidazole hydrochloride (20.5 mg). The reaction was stirred for 4 h, andthen quenched with aqueous saturated NH₄Cl. The mixture was extractedwith EtOAc, and the organic layer was washed with saturated aqueousNaCl, dried over Na₂SO₄, filtered, and concentrated. Silica gel flashcolumn chromatography of the residue (EtOAc/hexanes 10% to 50%) gaveprimary alcohol (303 mg, 84% yield). ¹H-NMR (600 MHz, C₆D₆) δ: 5.91 (1H,brs), 5.57 (1H, brd, J=1.2 Hz), 3.39 (2H, m), 3.25-3.34 (4H, m), 2.31(1H, m), 2.03 (1H, dd, J=14.7, 5.3 Hz), 1.86 (1H, m), 1.67-1.79 (2H, m),1.62 (2H, m), 1.13 (3H, d, J=6.5 Hz), 0.75 (3H, s), 0.72 (3H, s).

To a solution of primary alcohol (157 mg) in CH₂Cl₂ (2.2 mL) at roomtemperature was added NaHCO₃ (361 mg, 4.3 mmol) and Dess-Martinperiodinane (274 mg). After being stirred for 70 min, the reaction wasquenched with 10% aqueous Na₂S₂O₃. The mixture was extracted with EtOAc,washed with saturated aqueous NaCl, dried over Na₂SO₄, filtered, andconcentrated. Silica gel flash column chromatography of the residue(EtOAc/hexanes 20%) gave aldehyde (129 mg, 82% yield). ¹H-NMR (600 MHz,C₆D₆) δ: 9.44 (1H, t, J=1.5 Hz), 5.85 (1H, brs), 5.54 (1H, brd, J=1.2Hz), 3.20-3.32 (2H, m), 3.11-3.17 (2H, m), 2.25 (2H, m), 2.09 (1H, m),1.97 (1H, m), 1.88 (2H, dd, J=14.7, 6.5 Hz), 1.57 (1H, dd, J=15.0, 5.6Hz), 1.03 (3H, d, J=7.0 Hz), 0.76 (3H, s), 0.60 (3H, s).

To a solution of aldehyde (102 mg, 0.28 mmol) in t-BuOH (5.5 mL) and2-methyl-2-butene (2.2 mL) at room temperature was added a solution ofNaClO₂ (198 mg) and NaH₂PO₄—H₂O (304 mg) in H₂O (2.0 mL). After beingstirred for 2.5 h, diluted with H₂O (10 mL) and EtOAc (10 mL). Themixture was extracted with EtOAc, and the organic layer was washed withsaturated aqueous NaCl, dried over Na₂SO₄, filtered, and concentrated togive carboxylic acid, which was used for the next step without furtherpurification. ¹H-NMR (600 MHz, C₆D₆) δ: 5.86 (1H, brs), 5.54 (1H, brd,J=1.3 Hz), 3.28 (2H, m), 3.18 (2H, m), 2.25 (2H, m), 2.14 (2H, m), 2.04(1H, m), 1.94 (1H, dd, J=14.8, 5.6 Hz), 1.58 (1H, dd, J=14.7, 5.7 Hz),1.02 (3H, d, J=6.6 Hz), 0.75 (3H, s), 0.61 (3H, s).

To a solution of carboxylic acid in toluene (2.8 mL) and MeOH (0.28 mL)at room temperature was added TMSCHN₂ (2.0 M solution in Et₂O, 0.42 mL).After being stirred for 2 h, the reaction was concentrated. Silica gelflash column chromatography of the residue (EtOAc/hexanes 0% to 10%)gave P-3 (99.7 mg, 90% yield for 2 steps). ¹H-NMR (600 MHz, C₆D₆) δ:5.87 (1H, brs), 5.54 (1H, brd, J=1.8 Hz), 3.37 (3H, s), 3.19-3.32 (4H,m), 2.54 (2H, m), 2.09-2.26 (3H, m), 1.97 (1H, dd, J=14.7, 5.3 Hz), 1.60(1H, dd, J=14.7, 5.9 Hz), 1.04 (3H, d, J=6.5 Hz), 0.71 (3H, s), 0.66(3H, s).

Exemplary Synthesis of Halichondrins from Right Half/Left Half Fragments

Using the previously developed methods (See, e.g., J. Am. Chem. Soc.2012, 134, 893; 2014, 136, 5171) requisite enones can be prepared fromright and left haves bearing proper protecting groups. An exemplaryprocedure for halichondrin C is shown below. Using the same experimentalprocedures, halichondrins A and B can also be prepared. Likewise, theenones of norhalichondrins A-C can be prepared from the C39-C53iodoolefin of norhalichondrin.

To a solution of bis-TBS ether 1 (280 mg) in THF (5.5 mL) was added TBAFsolution (1 M in THF, buffered with 0.5 eq of imidazole-hydrochloride,1.1 mL) at room temperature. After stirring for 20 h at roomtemperature, solvent was removed under reduced pressure. The residue waspurified by silica gel flash column chromatography (DCM/hexanes 1:1 toEtOAc/hexanes 1/1 to 2/1 to EtOAc) to give diol.

To a stirred solution of the above diol (azeotropically dried withbenzene prior to use) in DCM (5.5 mL) and triethylamine (0.55 mL) at 0°C. was added p-nitrobenzoyl chloride (150 mg). The reaction was quenchedwith MeOH (0.2 mL) at 0° C. and the resultant mixture was furtherstirred for 15 min at room temperature. The reaction was diluted withEt₂O (8 mL) to precipitate white solid and the reaction flask wassonicated for five seconds. After filtration through a Celite pad (1 cm)and evaporation of the solvent, the crude material was purified bysilica gel flash column chromatography (DCM to EtOAc/hexanes ⅓ to ½) togive p-nitrobenzoate.

To a mixture of p-nitrobenzoate (azeotropically dried with benzene priorto use) and imidazole (110 mg) in DCM (3.0 mL) was added TES-Cl (0.14mL) at room temperature and the reaction mixture was stirred for 5 h atthe same temperature prior to the addition of H₂O. The aqueous phase wasextracted with EtOAc twice and combined organic phases were dried overNa₂SO₄, concentrated under reduced pressure. The obtained residue waspurified by silica gel flash column chromatography (EtOAc/hexanes ⅕ to⅓) to give TES ether (253 mg, 87% for 3 steps).

¹H NMR (600 MHz, C₆D₆) δ: 7.86 (2H, d, J=8.7 Hz), 7.72 (2H, d, J=8.7Hz), 5.76 (1H, dddd, J=16.7, 10.5, 5.4, 5.4 Hz), 5.18-5.14 (2H, m), 5.07(1H, d, J=1.2 Hz), 4.99-4.95 (2H, m), 4.88-4.83 (2H, m), 4.79 (1H, s),4.66-4.62 (2H, m), 4.58 (1H, ddd, J=10.8, 7.2, 5.1 Hz), 4.52 (1H, ddd,J=10.5, 10.5, 4.2 Hz), 4.38 (1H, dd, J=3.9, 2.1 Hz), 4.33 (1H, d, J=4.8Hz), 4.12 (1H, dd, J=6.6, 4.8 Hz), 4.05-3.98 (2H, m), 3.85-3.80 (3H, m),3.74-3.69 (2H, m), 3.50 (1H, dd, J=8.1, 3.9 Hz), 3.46 (1H, dd, J=6.3,4.2 Hz), 3.21 (1H, ddd, J=9.4, 2.7, 2.7 Hz), 3.09 (1H, dd, J=3.9, 3.9Hz), 2.78 (1H, dd, J=16.5, 7.5 Hz), 2.68-2.64 (1H, m), 2.56 (1H, dd,J=9.6, 1.8 Hz), 2.39-2.08 (14H, m), 1.98-1.84 (3H, m), 1.77-1.72 (1H,m), 1.58-1.56 (1H, m), 1.53-1.42 (4H, m), 1.39-1.30 (2H, m), 1.17 (3H,d, J=7.2 Hz), 1.13-1.07 (1H, m), 1.05 (9H, t, J=7.9 Hz), 1.01 (3H, d,J=6.6 Hz), 0.685 (6H, q, J=7.9 Hz).

Enone intermediates can be prepared by coupling left half and right halffragments using Ni/Cr coupling reaction as demonstrated:

To a solution of 2 (57.3 mg) in DCM (1.0 mL) were added NaHCO₃ (55.0 mg)and Dess-Martin periodinane (55 mg) at room temperature and the reactionmixture was stirred for 1 h at the same temperature. The reaction wasquenched by adding 10 wt % Na₂S₂O₃ aq. and sat. NaHCO₃ aq. and thenvigorously stirred for 30 min at room temperature. The aqueous phase wasextracted with DCM three times and combined organic phases were driedover Na₂SO₄. After evaporation of the solvent, the crude material waspurified by silica gel flash chromatography (EtOAc/hexanes 1:5 to 1:3 to1:2) to give aldehyde.

To a mixture of CrCl₂ (40.0 mg), (S)-i-Pr/Me/OMe sulfonamide (111 mg),and proton sponge (76.1 mg) in a glove box was added MeCN (3.2 mL) andstirred for 1 h at room temperature. In a separate flask, abovealdehyde, iodoolefin 3 (88.8 mg), NiCl₂-DMP (0.10 mg, doped in LiCl),LiCl (5.0 mg), were mixed together and the Cr-complex solution wastransferred to the flask. After stirring for 1 h at room temperature,the reaction was removed from the glove box and diluted with EtOAc (1.5mL) and added florisil and the mixture was stirred vigorously for 30min. The resultant mixture was filtered through silica gel plug, andconcentrated. The crude material was purified by silica gel flash columnchromatography (EtOAc/hexanes 1:10 to 1:5 to 1:3) to give allyl alcohol.

To a solution of the above allyl alcohol in DCM (2.0 mL) were addedNaHCO₃ (60 mg) and Dess-Martin periodinane (60 mg) at room temperatureand the reaction mixture was stirred for 1 h at room temperature. Thereaction was quenched with 10 wt % Na₂S₂O₃ aq. and sat. NaHCO₃ aq. andvigorously stirred for 30 min. The aqueous phase was extracted with DCMthree times and the combined organic phases were dried over Na₂SO₄ andconcentrated under vacuum. The residue was purified by silica gelpreparative TLC (EtOAc/hexanes 1:2) to provide 4 (51.2 mg, 45% in 3steps).

¹H NMR (600 MHz, C₆D₆) δ: 6.89 (1H, dd, J=16.2, 4.8 Hz), 6.48 (1H, dd,J=16.2, 1.8 Hz), 5.76 (1H, dddd, J=16.8, 10.2, 5.3, 5.3 Hz), 5.20 (1H,brs), 5.17 (1H, dd, J=17.4, 1.2 Hz), 5.10 (1H, brs), 4.99-4.95 (2H, m),4.86-4.82 (2H, m), 4.79 (1H, brs), 4.67 (1H, brs, J=10.2 Hz), 4.52 (1H,ddd, J=10.2, 10.2, 4.2 Hz), 4.38-4.37 (1H, m), 4.33 (1H, d, J=4.8 Hz),4.28-4.25 (1H, m), 4.15 (1H, dd, J=3.9, 3.9 Hz), 4.12 (1H, dd, J=6.6,4.8 Hz), 4.10-3.98 (5H, m), 3.93 (1H, brd, J=2.4 Hz), 3.85-3.71 (8H, m),3.48 (1H, dd, J=8.7, 4.5 Hz), 3.20-3.15 (2H, m), 3.12 (1H, dd, J=8.1,3.9 Hz), 3.09-3.03 (2H, m), 2.83-2.73 (3H, m), 2.57 (1H, dd, J=10.2, 1.8Hz), 2.53-2.46 (2H, m), 2.38-2.19 (9H, m), 2.14-2.10 (3H, m), 2.07-2.06(1H, m), 2.02-1.94 (3H, m), 1.86-1.83 (1H, m), 1.79-1.72 (2H, m),1.66-1.60 (2H, m), 1.55-1.49 (3H, m), 1.36-1.29 (2H, m), 1.21 (3H, d,J=7.2 Hz), 1.17 (9H, t, J=7.8 Hz), 1.09 (9H, s), 1.08 (9H, t, J=8.1 Hz),1.05 (9H, s), 1.02 (9H, s), 1.01 (9H, t, J=7.8 Hz), 1.09-0.995 (9H, m),0.861-0.817 (6H, m), 0.696 (6H, q, J=8.0 Hz), 0.586 (6H, q, J=7.6 Hz),0.293 (3H, s), 0.286 (3H, s), 0.169 (3H, s), 0.167 (3H, s), 0.094 (3H,s), 0.091 (3H, s).

An exemplary two-step deprotection/cyclization toward halichondrin C isshown below:

Buffered TBAF solution (0.5 M) was prepared by mixing TBAF (0.5 mL of 1M solution in THF:TCI (# T1125)), pivalic acid (Pv-OH, 0.3 mL of 1Msolution in DMF), and DMF (0.2 mL).

To a solution of enone (21.8 mg) in DMF (2.1 mL) was added the aboveTBAF solution (0.23 mL) via a syringe pomp at 0° C. over 1 h. Afterstirring for 1 h at the same temperature, the cooling bath was removedand the reaction mixture was stirred for 12 h (24 h for Nor-series) atroom temperature. The reaction was quenched by adding CaCO₃ (500 mg) andDOWEX 50WX8 (1.3 g: 200-400 mesh H⁺-form). After stirring for 1 h atroom temperature, the resulting suspension was diluted with EtOAc (ca. 2mL) and filtered through a pad of Celite, and the filter cake was washedwith EtOAc. The obtained solution was concentrated under reducedpressure, and the residue was dissolved in CH₂Cl₂ (2.3 mL).

To the solution was added PPTS (29 mg) at room temperature. Afterstirring for 2.5 h at the same temperature, Wakogel 50NH₂ (ca. 200 mg)and DCM (2.0 mL) was added. The resulting slurry was loaded onto acolumn of Wakogel 50NH₂ (neutral silica gel from Kanto Chemicals wasused for Nor-series), and purified (EtOAc/hexanes: ⅕ to ½ to 1/1 thenMeOH/EtOAc: 1/20 (100% EtOAc for Nor-series)), to furnish a 4:1 mixtureof allyl-protected halichondrin-C and its C38-epimer. The obtainedmixture was purified with HPLC (YMS-Pack C-18 column; MeCN/H₂O,gradient) to give allyl-protected halichondrin C (5.2 mg, 38% for 2steps) and C38-epi halichondrin C (1.3 mg, 9% for 2 steps).

¹H NMR (600 MHz, C₆D₆) δ: 5.75 (1H, dddd, J=17.3, 10.5, 5.3, 5.3 Hz),5.15 (1H, dddd, J=17.3, 1.7, 1.7, 1.7 Hz), 5.03 (1H, d, J=1.8 Hz), 4.97(1H, dddd, J=10.5, 1.5, 1.5, 1.5 Hz), 4.97-4.95 (1H, m), 4.93-4.88 (2H,m), 4.82 (1H, s), 4.63-4.56 (2H, m), 4.54-4.49 (1H, m), 4.39 (1H, dd,J=3.8, 1.8 Hz), 4.32 (1H, d, J=4.7 Hz), 4.19 (1H, s), 4.12 (1H, dd,J=6.6, 4.8 Hz), 4.08 (1H, ddd, J=10.5, 6.0, 6.0 Hz), 4.05-3.97 (3H, m),3.96-3.91 (1H, m), 3.87-3.76 (5H, m), 3.72-3.57 (6H, m), 3.55-3.50 (1H,m), 3.43-3.38 (1H, m), 3.35 (1H, t, J=2.6 Hz), 3.16 (1H, dd, J=2.6, 1.8Hz), 3.04-2.98 (1H, m), 2.76-2.64 (3H, m), 2.61 (1H, dd, J=9.7, 1.8 Hz),2.41-2.32 (3H, m), 2.32-2.09 (13H, m), 2.08-2.02 (3H, m), 2.01-1.94 (1H,m), 1.92-1.86 (2H, m), 1.85-1.78 (1H, m), 1.73-1.62 (4H, m), 1.57-1.41(5H, m), 1.39-1.25 (5H, m), 1.18 (3H, d, J=6.7 Hz), 1.16-1.09 (1H, m),1.06 (3H, d, J=7.0 Hz), 1.04 (3H, d, J=6.7 Hz), 0.95 (3H, d, J=7.0 Hz).

For the deprotection protocol of C11- and C12-hydroxyl groups, see: A.Yamamoto, A. Ueda, P. Brémond, P. S. Tiseni, and Y. Kishi, J. Am. Chem.Soc. 134, 893 (2012); A. Ueda, A. Yamamoto, D. Kato, and Y. Kishi, J.Am. Chem. Soc. 136, 5171 (2014).

For the protocol for isomerization of C38-epi halichondrin C tohalichondrin C, see: A. Ueda, A. Yamamoto, D. Kato, and Y. Kishi, J. Am.Chem. Soc. 136, 5171 (2014).

Other Embodiments

In the claims articles such as “a,” “an,” and “the” may mean one or morethan one unless indicated to the contrary or otherwise evident from thecontext. Claims or descriptions that include “or” between one or moremembers of a group are considered satisfied if one, more than one, orall of the group members are present in, employed in, or otherwiserelevant to a given product or process unless indicated to the contraryor otherwise evident from the context. The invention includesembodiments in which exactly one member of the group is present in,employed in, or otherwise relevant to a given product or process. Theinvention includes embodiments in which more than one, or all of thegroup members are present in, employed in, or otherwise relevant to agiven product or process.

Furthermore, the invention encompasses all variations, combinations, andpermutations in which one or more limitations, elements, clauses, anddescriptive terms from one or more of the listed claims is introducedinto another claim. For example, any claim that is dependent on anotherclaim can be modified to include one or more limitations found in anyother claim that is dependent on the same base claim. Where elements arepresented as lists, e.g., in Markush group format, each subgroup of theelements is also disclosed, and any element(s) can be removed from thegroup. It should it be understood that, in general, where the invention,or aspects of the invention, is/are referred to as comprising particularelements and/or features, certain embodiments of the invention oraspects of the invention consist, or consist essentially of, suchelements and/or features. For purposes of simplicity, those embodimentshave not been specifically set forth in haec verba herein. It is alsonoted that the terms “comprising” and “containing” are intended to beopen and permits the inclusion of additional elements or steps. Whereranges are given, endpoints are included. Furthermore, unless otherwiseindicated or otherwise evident from the context and understanding of oneof ordinary skill in the art, values that are expressed as ranges canassume any specific value or sub-range within the stated ranges indifferent embodiments of the invention, to the tenth of the unit of thelower limit of the range, unless the context clearly dictates otherwise.

This application refers to various issued patents, published patentapplications, journal articles, and other publications, all of which areincorporated herein by reference. If there is a conflict between any ofthe incorporated references and the instant specification, thespecification shall control. In addition, any particular embodiment ofthe present invention that falls within the prior art may be explicitlyexcluded from any one or more of the claims. Because such embodimentsare deemed to be known to one of ordinary skill in the art, they may beexcluded even if the exclusion is not set forth explicitly herein. Anyparticular embodiment of the invention can be excluded from any claim,for any reason, whether or not related to the existence of prior art.

Those skilled in the art will recognize or be able to ascertain using nomore than routine experimentation many equivalents to the specificembodiments described herein. The scope of the present embodimentsdescribed herein is not intended to be limited to the above Description,but rather is as set forth in the appended claims. Those of ordinaryskill in the art will appreciate that various changes and modificationsto this description may be made without departing from the spirit orscope of the present invention, as defined in the following claims.

1-103. (canceled)
 104. A compound of Formula (I-b-12) or (I-a-5):

or a salt thereof, wherein: R^(4a) is —CO₂R^(4d), wherein R^(4d) ishydrogen, optionally substituted alkyl, or an oxygen protecting group;R^(4b) is hydrogen, optionally substituted alkyl, or an oxygenprotecting group; R^(4c) is hydrogen, optionally substituted alkyl, oran oxygen protecting group; or R^(4b) and R^(4c) are taken together withthe intervening atoms to form an optionally substituted heterocyclicring; R^(PA) is optionally substituted alkyl or an oxygen protectinggroup; R^(1a) is hydrogen, halogen, optionally substituted alkyl,optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted carbocyclyl, optionally substituted heterocyclyl,optionally substituted aryl, or optionally substituted heteroaryl; andR^(1d) is independently hydrogen, halogen, optionally substituted alkyl,optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted carbocyclyl, optionally substituted heterocyclyl,optionally substituted aryl, or optionally substituted heteroaryl.105-191. (canceled)
 192. The compound of claim 104, wherein the compoundis of Formula (I-b-12), or a salt thereof.
 193. The compound of claim104, wherein the compound is of Formula (I-a-5), or a salt thereof. 194.The compound of claim 104, wherein R^(4d) is optionally substituted C₁₋₆alkyl.
 195. The compound of claim 104, wherein R^(4d) is unsubstitutedC₁₋₆ alkyl.
 196. The compound of claim 104, wherein R^(4d) is methyl.197. The compound of claim 104, wherein R^(4b) and R^(4c) are takentogether with the intervening atoms to form an optionally substitutedheterocyclic ring.
 198. The compound of claim 104, wherein R^(4b) andR^(4c) are taken together with the intervening atoms to form:


199. The compound of claim 104, wherein R^(PA) is an oxygen protectinggroup.
 200. The compound of claim 104, wherein R^(PA) is para-methoxybenzyl (PNB).
 201. The compound of claim 104, wherein R^(1a) is halogen.202. The compound of claim 104, wherein R^(1a) is —I.
 203. The compoundof claim 104, wherein R^(1d) is halogen.
 204. The compound of claim 104,wherein R^(1d) is —Cl.
 205. The compound of claim 192, wherein thecompound is the following:

or a salt thereof.
 206. The compound of claim 193, wherein the compoundis the following:

or a salt thereof.
 207. A compound of Formula (i-a-3):

or a salt thereof, wherein: R^(1a) is hydrogen, halogen, optionallysubstituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted carbocyclyl, optionallysubstituted heterocyclyl, optionally substituted aryl, or optionallysubstituted heteroaryl; and R^(1d) is independently hydrogen, halogen,optionally substituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted carbocyclyl, optionallysubstituted heterocyclyl, optionally substituted aryl, or optionallysubstituted heteroaryl.
 208. The compound of claim 207, wherein thecompound is the following:


209. A method of preparing a compound of claim 208, the methodcomprising a step of oxidizing a compound of the formula:

or a salt thereof.
 210. A method of preparing a compound of Formula(III-4), or a salt thereof, the method comprising a step of coupling acompound of Formula (III-5):

or a salt thereof, with a compound of Formula (III-6):

or a salt thereof, in the presence of a chromium catalyst and optionallyone or more additional catalysts, to form a compound of Formula (III-4):

or a salt thereof, wherein: R^(T3) is hydrogen, halogen, or substitutedor unsubstituted alkyl; R^(P5) is hydrogen, substituted or unsubstitutedalkyl, optionally substituted acyl, or an oxygen protecting group;R^(T5) is hydrogen, halogen, or substituted or unsubstituted alkyl;R^(Z5a) is hydrogen, substituted or unsubstituted alkyl, optionallysubstituted acyl, or an oxygen protecting group; each R^(A) isindependently hydrogen, optionally substituted alkyl, or an oxygenprotecting group; or optionally two R^(A) are joined to together withthe intervening atoms to form optionally substituted heterocyclyl; andeach instance of R^(B) is independently hydrogen or optionallysubstituted alkyl.